Prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways

Abstract

Cancer refers to the proliferation and multiplication of aberrant cells inside the human body, characterized by their capacity to proliferate and infiltrate various anatomical regions. Numerous biochemical pathways and signaling molecules have an impact on the cancer auto biogenesis process. The regulation of crucial cellular processes necessary for cell survival and proliferation, which are triggered by phytochemicals, is significantly influenced by signaling pathways. These pathways or components are regulated by phytochemicals. Medicinal plants are a significant reservoir of diverse anticancer medications employed in chemotherapy. The anticancer effects of phytochemicals are mediated by several methods, including induction of apoptosis, cessation of the cell cycle, inhibition of kinases, and prevention of carcinogenic substances. This paper analyzes the phytochemistry of seven prominent plant constituents, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, focusing on the involvement of the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. Hence, this review has examined a range of phytochemicals, encompassing their structural characteristics and potential anticancer mechanisms. It has underscored the significance of plant-derived bioactive compounds in the prevention of cancer, utilizing diverse molecular pathways. In addition, this endeavor also seeks to incentivize scientists to carry out clinical trials on anticancer medications derived from plants.

1 Introduction

Cancer is a pathological condition defined by the excessive and uncontrolled growth of abnormal cells within the human body. These abnormal cells exhibit the ability to proliferate and invade any region of the organism (Brown et al., 2023). Cancer is considered the second leading cause of mortality globally, following stroke and heart disease (Sun and Bhaskar, 2022). Cancer is classified based on the cellular genesis of the tumor. Carcinoma, a cancer that arises from the epithelial cells of the breast, prostate, lung, pancreas, and colon, is responsible for 90% of all cancer-related deaths in humans (Łukasiewicz et al., 2021). Lymphoma, on the other hand, is a cancer that affects immune organs like the spleen, white blood cells, and lymph nodes (Weledji and Orock, 2015). Leukemia is a cancer that affects the blood cells that make up the bone marrow (Bispo et al., 2020). Sarcoma is a cancer that affects the fibrous connective tissue of bones, cartilage, fatty tissue, muscles, and neurons (Vodanovich and M Choong, 2018). Lastly, germ cell tumors originate from pluripotent stem cells found in the testes and ovaries (Hong et al., 2021). Cell metabolism is intricately interconnected within a multifaceted biological network that encompasses various metabolites and ubiquitous mechanisms for sensing these compounds. Signal transduction and epigenetics of these pathways can be regulated by either endogenous or exogenous metabolites. Nevertheless, the occurrence of irregular metabolic reprogramming in cancer might result in atypical suppression and stimulation of metabolite sensing, hence playing a substantial role in the advancement of cancer (Schiliro and Firestein, 2021). Timely identification and efficient therapy enhance the likelihood of survival in cancer patients. Hence, it is imperative to develop a comprehensive strategy aimed at enhancing cancer prevention and treatment. Epidemiological and experimental studies have provided evidence supporting the notion that a substantial consumption of fruits, vegetables, or medicinal plants can effectively mitigate the prevalence of chronic degenerative diseases (Cruz et al., 2024). Moreover, the significance of maintaining a well-balanced diet in the context of cancer prevention has garnered considerable scholarly interest.

Medicinal plants have served as a valuable reservoir of diverse anticancer medications that are being employed in chemotherapy. Bioactive compounds, known as phytochemicals, play a crucial role in anticancer treatment (Yuan et al., 2022). These sources are secure, harmless, economical, and easily accessible, spanning from rural to urban areas and underdeveloped to developed nations (Irianti et al., 2020). Hence, there is growing interest in exploring the possible anticancer properties of herbal substances. Chemoprevention refers to the application of both natural and synthetic chemicals for impeding or decelerating the progression of cancer through the inhibition or disruption of specific molecular signaling pathways (G et al., 2021). The investigation of the impact of phytochemicals on cellular signaling is presently a subject of contemporary scholarly research. These substances have distinct modes of action against tumors. Bioactive compounds (phytochemicals) play a crucial role in the field of anticancer treatment (Situmorang et al., 2022a). The gynogenesis movement is impacted by multiple biochemical pathways and signaling molecules. Signaling pathways and molecular networks play a crucial role in the regulation of vital cellular processes that are required for the survival and proliferation of cells. The etiology of cancer necessitates a correlation with distinct biological pathways (Fawaz et al., 2023). Researchers persist in employing this methodology to further the progress of molecular therapy. Various molecular biology methodologies have been developed to detect and treat cancer, including the targeting of cancer stem cell pathways for treatment, utilization of retroviral therapy, suppression of oncogenes, and the alteration of tumor suppressor genes (Simanullang RH. et al., 2022). The regulation of cell proliferation, differentiation, survival, apoptosis, invasion, migration, angiogenesis, and metastatic spread of cancer cells is connected with various signaling pathways, including mTOR, PI3K, protein kinase B (Akt), MAPK/ERK, Wnt, Notch, and Hedgehog (Kciuk et al., 2022). The anticancer activities are induced by phytochemicals through the regulation of certain pathways or components.

Multiple independently conducted investigations have indicated that phytochemicals induce anticancer effects through various pathways (Choudhari et al., 2019). Nevertheless, there is a lack of detailed reporting regarding the phytochemical composition of seven plant components, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, in relation to their potential as anticancer agents (Simanullang et al., 2022b). There are no reports regarding the regulation of cell proliferation and inhibition of angiogenesis and metastasis through the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. Thus, this review has examined different phytochemicals, including their structures and probable anticancer mechanisms. As a result, it offers comprehensive knowledge on the potential of natural anticancer resources.

2 Role of phytochemicals and antioxidants in inhibiting the resistance of cancer to therapy

Utilizing phytochemicals for cancer chemoprevention is the preferred method for managing cancer. Investigating novel plant-derived chemicals with anticancer characteristics is a crucial objective in pharmacological research as it enables the discovery of new therapeutic targets (Efferth et al., 2017). This review highlights specific chemicals that exhibit potential as effective chemo-preventive agents for cancer. It is worth noting that the consumption of foods containing these bioactive compounds has demonstrated both protective and therapeutic benefits against different forms of cancer (Bakrim et al., 2022). The efficacy of chemotherapy and radiotherapy is enhanced by chemo-preventive medicines through regulation of various signal transduction pathways. Given the significant involvement of oxidative stress in the development of numerous malignancies, the potential of substances with antioxidant properties as a preventive measure against cancer is worth considering (Qi et al., 2022). Plants are rich in antioxidant phytochemicals, which encompass a diverse range of molecules (Simanullang et al., 2022c). These substances have distinct modes of action against tumors. Bioactive compounds (phytochemicals) play a crucial role in the field of anticancer treatment. Medicinal plants or their derivatives currently constitute over 70% of anticancer chemicals, making them the primary focus in the development of anticancer medications (Talib et al., 2020). The anticancer properties of plants are attributed to seven primary bioactive compounds: alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins. Alkaloids are significant chemical substances that constitute a plentiful resource for the exploration of new drugs. Several alkaloids derived from medicinal plants and herbs have demonstrated antiproliferative and anticancer properties against a diverse range of malignancies, both in laboratory settings (in vitro) and in living organisms (in vivo) (Lu et al., 2012). Vinblastine, vinorelbine, vincristine, and vindesine have been effectively formulated as pharmaceutical agents for the treatment of cancer. Tannins demonstrate a wide range of therapeutic advantages, including their ability to combat cancer, act as an antioxidant, reduce inflammation, and protect the nervous system (Dhyani et al., 2022). Flavonoids are widely recognized for their efficacy as antioxidants and their ability to inhibit angiogenesis. Numerous studies have documented the inhibitory effects of flavonoids on the metabolic activation of carcinogens, hence impeding the proliferation of aberrant cells that have the potential to differentiate into malignant cells (Wang et al., 2022). Phenols in foods have multiple functions, including acting as antioxidants to eliminate cancer-causing free radicals, activating cytoprotective enzymes involved in detoxifying foreign substances, and regulating signal transduction systems (Aghajanpour et al., 2017). The involvement of antioxidants in the activation of the Keap1/Nrf2/ARE pathway leads to heightened levels of phase 2 detoxification enzymes and antioxidant enzymes (Mendonca and Soliman, 2020). The anticancer effects of terpenes may be attributed to their capacity to regulate several signaling pathways associated with cellular proliferation, death, and angiogenesis. The anticancer effects of terpenes may also be attributed to their ability to induce oxidative stress and DNA damage in cancer cells (Wróblewska-Łuczka et al., 2023). Steroids encompass a class of naturally occurring organic compounds that have steroidal anticancer properties. This class of chemicals exhibits a wide range of structural molecular diversity and possesses the capacity to interact with diverse biological targets and pathways. Saponins exhibit several anticancer properties, such as inhibiting cell growth, impeding metastasis, inhibiting angiogenesis, and reversing multidrug resistance (MDR) (Elekofehinti et al., 2021). These effects are caused by the initiation of apoptosis, stimulation of cell differentiation, modulation of the immune system, binding of bile acids, and improvement of cell proliferation caused by carcinogens.

Oxidative stress plays a crucial role in the harmful effects of environmental toxicity in cancer development, and reactive oxygen species (ROS) are produced in response to both internal and external triggers (Chang et al., 2015). Reactive oxygen species (ROS) such as superoxide radicals (O₂−.), hydrogen peroxide (H₂O₂), singlet oxygen (1O₂), and hydroxyl radicals (HO.) are harmful to cells and have been linked to the development of different human diseases, including cancer (Afzal et al., 2023). Several carcinogens exert their effects by generating reactive oxygen species (ROS) during their metabolic process (Afzal et al., 2023). Oxidative DNA damage is a significant factor in the development and advancement of carcinogenesis as it can cause mutations (Martemucci et al., 2022). Hence, the crucial role of antioxidants in counteracting elevated levels of reactive oxygen species (ROS) is significant in the context of numerous disorders, including different forms of cancer (Afzal et al., 2023). Epidemiological studies form the primary basis for establishing the correlation between dietary antioxidants and non-communicable diseases, such as cancer. These studies indicate that plant foods and phytochemicals have the capacity to prevent cancer. Certain phytochemicals have the ability to function as both antioxidants and prooxidants (Situmorang and Ilyas, 2018). They can generate reactive oxygen species (ROS) and induce oxidative stress at high levels, particularly when iron and copper are present. Polyphenols, including quercetin, epicatechin, epigallocatechin-3-gallate (EGCG), and gallic acid, have been found to generate reactive oxygen species (ROS) in cell models due to their prooxidant properties (Yang et al., 2020). Phytochemicals are widely recognized for their antioxidant properties, but they can also display prooxidant activity under specific circumstances, such as when administered in excessive amounts or in the presence of metal ions (Yang et al., 2020). The concentration of phytochemicals plays a crucial role in determining whether they exhibit prooxidant or antioxidant activity (Situmorang et al., 2021a). Studies using cell models have highlighted the prooxidant activity of polyphenols, which are known for their antioxidant properties. Specifically, compounds such as quercetin, epicatechin, and epigallocatechin-3-gallate (EGCG) have been found to demonstrate this prooxidant activity. At elevated concentrations, such as 50 μM, quercetin enhances the generation of superoxide radicals (O₂−) in isolated mitochondria and cell culture medium (Yang et al., 2020; Safi et al., 2021). Previous research has demonstrated that quercetin can decrease cell viability and thiol content, as well as impair overall antioxidant capacity and the activities of SOD, CAT, and glutathione transferase at higher concentrations (Safi et al., 2021). High amounts of flavonoids can generate reactive oxygen species (ROS) through processes such as autoxidation and redox cycles, as seen in quercetin (Safi et al., 2021).

Dietary phytochemicals can activate many cell signaling pathways, and the specific route triggered by a molecule can vary depending on the type of cell (Hun Lee et al., 2013). Elevated levels of pro-apoptotic p53 and reduced levels of key pro-survival factors, such as epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NF-κB), activator protein 1, signal transducers and activators of transcription (STAT), survivin, metalloproteinases 2 and 9, vascular endothelial growth factor (VEGF), and B-cell leukemia/lymphoma 2 (Bcl-2), are observed under optimal conditions when phytochemicals are administered (Gupta et al., 2012). The effectiveness of phytochemicals in cancer treatment stems from their capacity to influence many signaling pathways concurrently, hence facilitating apoptosis, impeding cellular proliferation and invasion, sensitizing malignant cells, and enhancing immune system functionality (George et al., 2021). The synergistic effect of cytotoxic anticancer drugs and phytochemical inhibitors can synergistically reduce tumor growth (Cheon and Ko, 2022). The phytochemical composition of the seven primary plant constituents, namely, flavonoids, alkaloids, terpenoids, steroids, saponins, phenol, and tannins, as anticancer agents is shown in Supplementary Table S1.

3 Role of phytochemicals in the MAPK/ERK pathway

The MAPK/ERK pathway is a cellular protein chain responsible for transmitting signals from cell surface receptors to DNA within the cell nucleus. The development of certain human disorders, including as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and several types of cancer, has been associated with deviations from strict regulation of the MAPK signaling pathway (Albert-Gascó et al., 2020). This particular route encompasses a multitude of proteins, including mitogen-activated protein kinase (MAPK, formerly known as ERK). These proteins engage in communication by introducing phosphate groups to adjacent proteins, thus functioning as active or inactive switches. MAPKs represent a group of serine/threonine protein kinases that exhibit a high degree of conservation. These kinases play a crucial role in numerous essential cellular processes, including but not limited to proliferation, differentiation, motility, stress response, apoptosis, and survival (Chen et al., 2021). There have been characterizations of at least three MAPK families, namely, extracellular signal-regulated kinase (ERK), Jun kinase (JNK/SAPK), and p38 MAPK. The aforementioned effects are achieved through the modulation of cell-cycle machinery and other proteins associated with cell proliferation (Min and Lee, 2023). Figure 1 investigates the function of this system in conjunction with other signaling pathways to regulate the proliferation of cancer cells. MAPK activation is initiated in a multistep process through the stimulation of receptor tyrosine kinase (RTK) in the MAPK/ERK signaling pathway. The protein kinase activity of RAF kinase is facilitated by the activation of Ras. The phosphorylation and activation of MEK (MEK1 and MEK2) is facilitated by RAF kinase. ERK is activated and phosphorylated by MEK (Santarpia et al., 2012). The role of the MAPK/ERK pathway in the translation of extracellular signals to cellular responses has been demonstrated to be significant. The protein kinase cascade encompasses the presence of MAP kinase (Cargnello and Roux, 2011). The cascade comprises a minimum of three enzymes that are sequentially activated: MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAP kinase (MAPK). The MAPK/ERK pathway is involved in multiple processes associated with cancer, such as proliferation, invasion, metastasis, angiogenesis, and apoptosis inhibition. The MAPK/ERK pathway has a significant impact on encouraging cancer cell proliferation and preventing apoptosis due to its diverse actions (Kciuk et al., 2022). For instance, the compound β-carboline has been observed to impede cell growth and trigger apoptosis in SGC-7901 cells. This disruption of the PTEN and ERK balance leads to the inhibition of the MAPK/ERK signaling pathway, ultimately resulting in apoptosis in SGC-7901 cells (Qin et al., 2022). Berberine has the ability to block the EGFR/Raf/MEK/ERK pathway, hence suppressing the aging process in human glioblastoma cells. Sinomenine suppresses the growth of many cancer cells (Liu et al., 2015). The phosphorylation of ERK1/2 and p38 is enhanced by the presence of sinomenine hydrochloride (SH). The phosphorylation of ERK1/2 was considerably increased by the benzo alkaloid chelerythrine chloride, while the phosphorylation of Akt was lowered in a dose-dependent manner (Peng et al., 2023). Table 1 presents the mechanism of action of various phytochemical compounds in the MAPK/ERK pathway in cancer.

FIGURE 1

4 Role of phytochemicals in the TNF-signaling pathway

The activation of signaling pathways for cell survival, death, and differentiation is facilitated by the tumor necrosis factor (TNF) superfamily of cytokines. TNF signaling has witnessed a growing trend in the therapeutic management of individuals afflicted with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), as well as rheumatologic and dermatological conditions such as rheumatoid arthritis (RA), juvenile idiopathic arthritis, and cancer (Evangelatos et al., 2022). The activation of signal transduction pathways that promote apoptosis can occur in cancer illnesses by the recruitment of death domains (DDs) containing adapters, such as the Fas-associated death domain (FADD) and TNFR-associated DD (TRADD), via TNF signaling (Mak and Yeh, 2002). The activation of transcription factors, such as NF-kappa B and JNK, can be facilitated by the recruitment of TRAF family proteins. This activation promotes cell survival and differentiation, as well as immunological and inflammatory responses. Tumor necrosis factor ligands and receptors were included based on their sequence and structure. The TNF-related ligand is classified as a type II transmembrane protein, characterized by an internal N terminus and an external C terminus, known as the “TNF homology domain” (THD). An essential characteristic of the receptor is the presence of a cysteine-rich domain (CRD), which is composed of three disulfide connections encircling the core motif CXXCXXC, resulting in the formation of an elongated molecule (Suo et al., 2022). Figure 2 illustrates the mechanism by which tumor necrosis factor (TNF) exerts its effects via the tumor necrosis factor receptor (TNFR), hence participating in the extrinsic pathway for induction of apoptosis. The association between the TNFR and procaspases is mediated by adapter proteins such as FADD and TRADD. These adapter proteins have the ability to cleave dormant procaspases, thus initiating the caspase cascade. This cascade ultimately leads to irreversible induction of death in cells (Elmore, 2007). Studies on the apoptotic pathway have identified a malfunction in the breakdown of lysosomal DNA, which triggers macrophages to generate cytokines like IFN² and TNF, without relying on Toll-like receptors (TLRs) (Brouckaert et al., 2004). The interaction between tumor necrosis factor and tumor cells initiates cytolysis, which is the process of cell death. The inflammatory response can be enhanced by tumor necrosis factor (Li and Beg, 2000). The mechanism of action of various phytochemical compounds in the TNF-signaling pathway in cancer is shown in Table 2.

FIGURE 2

5 Role of phytochemicals in the death receptor pathways

Death receptors are receptors located on the surface of cells that send signals triggering apoptosis. The involvement of death receptors in the process of apoptosis of inflammatory cells, both in vivo and in vitro, is of significant importance in various disorders, including inflammation, hypertension, and cancer (Green, 2022). In certain cases ,T lymphocytes and macrophages exhibit the presence of several TNFR/ligands within plaques (Situmorang et al., 2022b). The TNFR pathway has been linked to the death of T cells and macrophages (Situmorang P. C. et al., 2024). These receptors, like TNFR, are stimulated by specific ligands and play a critical role in instructive apoptosis (Siegmund et al., 2016). Death receptors are classified under the superfamily of tumor necrosis factor receptor (TNFR) genes (Hehlgans and Pfeffer, 2005). So far, eight members of the death receptor family have been identified: TNFR1 (also referred to as DR1, CD120a, p55, and p60), CD95 (also referred to as DR2, APO-1, and Fas), DR3 (also referred to as APO-3, LARD, TRAMP, and WSL1), TRAILR1 (also referred to as DR4 and APO-2), TRAILR2 (also referred to as DR5, KILLER, and TRICK2), DR6, ectodysplasin A receptor (EDAR), and nerve growth factor receptor (NGFR). The death receptors can be identified by the presence of a cytoplasmic region known as the death domain (DD), which has around 80 residues (Hoffmann et al., 2009). In the context of cancer (Figure 3), the activation of these receptors by certain ligands leads to the recruitment of several molecules to the death domain, subsequently initiating a signaling cascade. There are two distinct forms of death receptor signaling complexes. The first group comprises death-inducing signaling complexes (DISCs) that lead to the activation of caspase-8, a pivotal component in the signaling transduction pathways that mediate apoptosis (Gnesutta and Minden, 2003). DISCs are generated on the CD95, TRAILR1, or TRAILR2 receptors. The second category consists of TNFR1, DR3, DR6, and EDAR. The process entails the recruitment of several molecules that assist the translation of signals related to apoptosis and cell survival (Schneider-Brachert et al., 2013). The mechanism of action of various phytochemical compounds in the death receptor pathway in cancer is shown in Table 3.

FIGURE 3

6 Role of phytochemicals in the p53 pathway

The p53 tumor suppressor is a prominent mechanism involved in apoptosis signaling. Cell loss in various neurological illnesses, such as Alzheimer’s disease, Parkinson’s disease, hypertension, stroke, and cancer, may be attributed to p53-related apoptosis, which is a frequently observed process (Wolfrum et al., 2022). In response to genotoxic or cellular stress, the p53 protein functions as a nuclear transcription factor, exerting regulatory control over the expression of several genes associated with apoptosis, growth arrest, or senescence (Mijit et al., 2020). E3 ubiquitin ligases, such as MDM2, exert a negative regulatory effect on p53 protein levels in cancer (Figure 4). The proteasome-dependent degradation of p53 is facilitated by the E3 ligase, which enhances ubiquitination. In response to various stress stimuli, such as DNA damage, nucleolar stress, metabolic stress, and oncogenic stress, the levels of p53 protein exhibit stability. The cytoplasmic connections between P53 and Bcl-2 family proteins have been observed to facilitate the process of apoptosis. It was demonstrated in the late 1980s and early 1990s that the introduction of the wild-type p53 gene into different human tumor cells resulted in the induction of apoptosis and suppression of cell growth (Dhokia et al., 2022). A curative response was observed in a mouse model system where the function of p53 was precisely reactivated in the tumor. The activation of p53 triggers cell-cycle arrest, facilitating DNA repair and/or apoptosis to inhibit the proliferation of cells with significant DNA damage (Chen, 2016). This is achieved via transactivating target genes that are involved in the initiation of cell cycle arrest and/or apoptosis. The mechanism of action of various phytochemical compounds in the p53 pathway in cancer is shown in Table 4.

FIGURE 4

7 Role of phytochemicals in the p38 pathway

The involvement of p38 MAP kinase (MAPK) in signaling cascades governing cellular reactions to cytokines and stress has been observed (Falcicchia et al., 2020). Four p38 MAP kinases have been found in mammals, namely, p38-α (MAPK14), p38-β (MAPK11), p38-γ (MAPK12/ERK6), and p38-ι (MAPK13/SAPK4). Just like the SAPK/JNK pathway, the activation of p38 MAP kinases occurs in response to several cellular stressors and various illnesses, including osmotic shock, inflammatory cytokines, lipopolysaccharide (LPS), UV light, growth factors, hypertension, and cancer (Asih et al., 2020). Furthermore, the activation of p38 is indirectly induced by oxidative stress and GPCR stimulation (Situmorang et al., 2023). The regulation of downstream targets, such as various kinases, transcription factors, and cytosolic proteins, is governed by p38 MAPK in the context of cancer (Huang et al., 2024). The kinases considered in this study are MAPKAPK2, MAPKAPK3, PRAK, MSK1, and MNK ½ (Figure 5). P38 phosphorylates several crucial transcription factors, such as the tumor suppressor protein p53, CHOP (C/EBP homologous protein), STAT1 (signal transducer and activator of transcription-1), CREB (cAMP response element-binding protein), and Max/Myc complex (Koul et al., 2013). The p38 MAPK pathway plays a crucial role in regulating the production of pro-inflammatory cytokines at both the transcriptional and translational levels. Consequently, several elements within this system hold promise as possible therapeutic targets for autoimmune and inflammatory disorders (Ganguly et al., 2023). The p38 pathway plays a crucial role in controlling cell growth and suppressing tumor growth by influencing many regulators of the cell cycle. The tumor-suppressing role of the p38 pathway suggests that several elements of the p38 pathway hold promise as possible targets for innovative cancer treatments (Martínez-Limón et al., 2020). The mechanism of action of various phytochemical compounds in the p38 pathway in cancer is shown in Table 5.

FIGURE 5

8 Role of phytochemicals in the actin dynamics signaling pathways

G protein-coupled receptors (GPCRs), integrins, and receptor tyrosine kinases (RTKs) are involved in the regulation of actin dynamics by extracellular signals. G protein-coupled receptors (GPCRs) encompass a diverse group of protein receptors that detect extracellular chemicals and initiate intracellular signal transduction pathways, ultimately leading to physiological responses (Cheng et al., 2023). The formation of aberrant thin filaments and the disruption of muscular contraction might result from dysfunctional actin–ATP binding, hence causing muscle weakening and various manifestations of actin accumulation myopathy (Dowling et al., 2021). No ACTA1 gene mutation has been detected in certain individuals with actin accumulation myopathy. In addition to muscular issues, actin dynamics signaling pathways also contribute to the development of cancer. Transmembrane receptors known as integrins serve as intermediaries between cell–cell interactions and the extracellular matrix (ECM) of a cell. In cancer, integrins initiate signaling transduction pathways that affect the cell interior, including the chemical composition and mechanical state of the extracellular matrix (ECM) (Jo et al., 2020). This leads to transcriptional activation, which in turn regulates several cellular processes such as cell cycle regulation, cell shape, the cell’s ability to move, and the addition of additional receptors to the cell membrane (Pang et al., 2023). RTKs, or receptor tyrosine kinases, belong to the extensive group of protein tyrosine kinases. Tyrosine kinase receptors encompass a diverse array of proteins, including EGFR, PDGFR, MCSFR, IGF1R, INSR, NGFR, FGFR, VEGFR, and HGFR (Figure 6). Rho is responsible for modulating intracellular signals that control the cell’s response to external stimulus. Rho is a constituent of the Ras superfamily of tiny GTP-binding proteins that has significant involvement in various biological processes, including the organization of the actin cytoskeleton, dynamics of microtubules, transcription of genes, transformation of cancer cells, development of the cell cycle, adhesion, and epithelial wound repair (Zubor et al., 2020). The activation of GEF (guanine nucleotide exchange factor) is seen (Ilyas et al., 2022). The protein kinase effectors ROCK and PAK are located downstream. The occurrence of immunological diseases, developmental abnormalities, and cancer often involves the disruption of cytoskeletal signaling, leading to the cessation of production of extracellular stimuli and cellular responses (Miller and Zachary, 2017). The mechanism of action of various phytochemical compounds in actin dynamics signaling pathways in cancer is shown in Table 6.

FIGURE 6

9 Role of phytochemicals in the autophagy pathways

Autophagy is a cellular recycling mechanism characterized by the dynamic destruction of cytoplasmic contents, aberrant protein aggregates, and excess or damaged organelles through the autophagosome–lysosome process (Gómez-Virgilio et al., 2022). Impaired autophagy function is linked to NAFLD, diabetes, AKD/CKD, heart failure, IBD, and neurodegenerative disorders. These models provide comprehensive data on initial effectiveness, toxicity, pharmacokinetics, and safety, which aids in determining whether a molecule should be further developed for the purpose of conducting clinical studies (Situmorang et al., 2021b; Situmorang et al., 2021c). Nevertheless, in the context of cancer, both the inhibition and augmentation of autophagy significantly contribute to the advancement of the disease via several mechanisms. The activation of mTOR (Akt and MAPK signaling) in cancer leads to the suppression of autophagy, while the negative regulation of mTOR (AMK and p53 signaling) increases autophagy (Verma et al., 2021). ULK functions in a manner comparable to that of yeast Atg1, operating in the downstream region of the mTOR complex. The formation of a substantial complex between ULK, Atg13, and the scaffolding protein FIP200 is observed. The induction of autophagy necessitates the presence of the class III PI3K complex, which comprises hVps34, beclin 1 (the mammalian counterpart of yeast Atg6), p150 (the mammalian counterpart of yeast Vps15), and Atg14-like protein (Atg14L or Barkor) or ultraviolet irradiation resistance-associated gene (UVRAG) (Tran et al., 2021). Rubicon exerts inhibitory effects on the activity of PI3K class III lipid kinase and counteracts the effects of Atg14L, a protein that enhances class III PI3K activity. Autophagosome formation is regulated by the Atg12-Atg5 and LC3-II (Atg8-II) complexes, which are controlled by the Atg gene. Atg12 undergoes conjugation with Atg5 through an ubiquitin-like process, which necessitates the involvement of Atg7 and Atg10 (enzymes with E1-and E2-like properties, respectively). The Atg12–Atg5 conjugate subsequently has a noncovalent interaction with Atg16, resulting in the formation of a substantial complex (Hu and Reggiori, 2022). The protease Atg4 cleaves the C terminus of the second complex, LC3/Atg8, resulting in the formation of cytosolic LC3-I. The process of conjugating LC3-I to phosphatidylethanolamine (PE) involves a ubiquitin-like reaction that necessitates the involvement of Atg7 and Atg3, which are enzymes with E1-and E2-like properties, respectively (Agrotis et al., 2019). LC3-II, a lipidated variant of LC3, adheres to the membrane of autophagosomes (Figure 7). Autophagy and apoptosis have both positive and negative associations, with significant intercommunication observed between these two biological processes. The process of autophagy is a survival strategy that is activated when nutrients are scarce (Xi et al., 2022). However, an excessive amount of autophagy can result in cell death, which is a separate process from apoptosis in terms of its morphology. Autophagy is also induced by other pro-apoptotic signals, including TNF, TRAIL, and FADD. Furthermore, Bcl-2 exerts inhibitory effects on beclin 1-dependent autophagy (Ilyas et al., 2021), thus serving as a dual regulator of both pro-survival and anti-autophagic processes. The mechanism of action of various phytochemical compounds in autophagy pathways in cancer is shown in Table 7.

FIGURE 7

10 Phytochemicals in clinical trials as anticancer agents

During the practical process of drug development, employing meticulous preclinical screening models can generate promising lead compounds for the development of anticancer drugs. These models provide comprehensive data on initial effectiveness, toxicity, pharmacokinetics, and safety, which aids in determining whether a molecule should be further developed for the purpose of conducting clinical studies (Situmorang et al., 2021b). In the present review, a substantial body of evidence pertaining to the effectiveness of several phytochemicals has been amassed. Clinical research has demonstrated that P. ginseng effectively decreases the occurrence of cancer and exhibits advantageous benefits in individuals with cancer (Chen S. et al., 2014). Previous research has demonstrated that the consumption of fresh ginseng slices, juice, or tea has been associated with a reduced likelihood of developing many types of cancer, such as those affecting the pharynx, larynx, esophagus, stomach, colorectal, pancreatic, liver, lung, and ovarian regions (Lim et al., 2016). The presence of resveratrol in grape powder does not exhibit the ability to inhibit the Wnt pathway in colon cancer. However, it does demonstrate the capacity to inhibit the expression of Wnt target genes in the normal colonic mucosa of individuals diagnosed with colorectal cancer. This implies that resveratrol has advantageous properties in the onset and spread of colon cancer due to its modulation of Wnts and their downstream effectors, which play a crucial role in regulating various processes associated with tumor initiation, tumor growth, cell death, and metastasis (Jin et al., 2016). Furthermore, empirical investigations have demonstrated that flavonoids exhibit antiproliferative and apoptotic properties against diverse tumor cell lines, such as human lymphoma, breast cancer, osteosarcoma, and transformed hepatoma cells. A study including 250 urine samples obtained from Chinese women residing in Shanghai demonstrated a correlation between elevated excretion of total isoflavonoids and total lignans and a decreased likelihood of developing breast cancer (Situmorang PC. et al., 2024). Research has demonstrated that the incorporation of phytosterols into one’s diet can effectively mitigate the likelihood of developing obesity, diabetes, and cancer risk factors. The efficacy of phytosterols as anticancer agents has been demonstrated in several in vivo investigations, employing diverse cancer cell lines and animal models (Dai et al., 2002). Based on the above explanation, it is evident that numerous phytochemical constituents have been subjected to research and have progressed to the clinical trial phase. Herbal phytochemicals promote autophagy, a process by which cells undergo halting of aberrant growth and development. Autophagy is induced by the downregulation of the AKT and mTOR pathways in cancer cells (Ahmed et al., 2022). Hence, phytochemicals modulate antitumor effects in tissues via controlling inflammation, angiogenesis, invasion, and metastasis. The signaling pathways that phytochemicals use to halt carcinogenesis are illustrated in Figure 8.

FIGURE 8

11 Nanoformulation and green synthesis improve cancer-fighting natural chemicals

Various drug delivery technologies, such as synthetic polymers, microcapsules, and liposomes, possess the characteristic of enhancing medication bioavailability and promoting drug accumulation at the intended location. Herbal administration of anticancer medications is crucial since it minimizes or eliminates any adverse effect on healthy tissues. The utilization of nanoformulations is prevalent in the development of sunscreens, antibacterial medications, cholesterol biosensors, and dietary modulators for the purpose of managing diabetes and hyperlipidemia (Khafaga et al., 2023). Furthermore, it is imperative for the drug to possess functional groups that facilitate further alterations aimed at regulating drug release or binding to the target unit. The potential application of silver nanoparticle-based nanosystems as carriers for several therapeutic chemicals, including those possessing anti-inflammatory, antioxidant, antibacterial, and anticancer characteristics, has been the subject of investigation (Burdusel et al., 2018).

The present methodology for synthesizing nanoparticles in an environmentally sustainable manner is distinctive and time-efficient. Extensive research has been carried out on silver nanoparticles (AgNPs) due to their potential anticancer properties, as evidenced by multiple studies on human cancer. AgNPs exhibit significant potential as a highly efficient mechanism for delivering antitumor drugs. AgNPs address these limitations by mitigating adverse effects and enhancing the efficacy of cancer treatment. AgNPs have great potential as pharmaceuticals, as evidenced by the favorable outcomes of prior research and their affordability (Takáč et al., 2023). Several previously documented phytochemicals have demonstrated the potential of phytochemicals as cancer medicines because of their ability to form ionic or covalent connections with gold nanoparticles (AuNPs) and undergoing physical absorption. A hybrid system was formed by covalently linking polyacrylamide/dextran nano-hydrogel to silver nanoparticles, resulting in an in vitro release of 98.5%. Nevertheless, the utilization of AgNPs as therapeutic agents is hindered by certain inherent challenges pertaining to toxicity (Yusuf et al., 2023). In order to surmount these challenges and facilitate their application in preclinical trials involving people or other organisms, it is imperative that AgNPs exhibit biocompatibility, non-toxicity, and the absence of adverse effects. The selection of various mechanistic pathways, such as mitochondrial disruption, DNA fragmentation, cell membrane disruption, cellular signaling pathway disruption, enzyme activity changes, and reactive oxygen species (ROS), by AgNPs holds significant promise for therapeutic applications due to their ability to control the size, shape, and function of the corona surface. Utilizing phytochemicals found in plant extracts, AgNPs were produced by green synthesis for potential cancer treatment. Furthermore, this study also presents recent advancements and accomplishments in the application of silver nanoparticles (AgNPs) produced by green synthesis in the field of cancer therapy (Ratan et al., 2020). It also suggests probable mechanisms through which these nanoparticles may exhibit anticancer and cytotoxic properties. The comprehension of the molecular mechanisms behind the therapeutic effectiveness of AgNPs holds promise for the development of targeted therapies and treatments for cancer, hence presenting a promising avenue for cancer treatment (Wahi et al., 2023).

12 Conclusion

Cancer is characterized by abnormal cell metabolism, which is considered a biological indicator. The preferred approach for cancer treatment is the use of plant compounds for chemoprevention. The observed preventive and therapeutic advantages of these bioactive chemicals against different types of cancer can be attributed to their ability to modulate signal transduction pathways. The consideration of compounds possessing antioxidant properties as a preventive intervention against cancer is warranted due to the substantial role of oxidative stress in the pathogenesis of diverse malignant illnesses. Seven primary bioactive chemicals, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, found in plants have anticancer activities. These compounds play a significant role in modulating cell growth. The process of angiogenesis and metastasis inhibition in cancer is mediated by various mechanisms, including the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. In the context of combating cancer resistance, novel molecular processes necessitate the exploration of novel multitargets. Phytochemical substances, whether transformed into natural small molecules or nanostructured formulations, exhibit considerable potential as multitarget agents due to their reduced side effects and enhanced efficacy. This phenomenon not only exerts an impact on the proliferation of malignant cells but also offers practical insights for the investigation of therapeutic agents that specifically target tumors, hence paving the way for novel avenues in the realm of cancer prevention and therapy.

References

• 1

  Abbaspour Babaei M. Zaman Huri H. Kamalidehghan B. Yeap S. K. Ahmadipour F. (2017). Apoptotic induction and inhibition of NF-κB signaling pathway in human prostatic cancer PC3 cells by natural compound 2,2’-oxybis (4-allyl-1-methoxybenzene), biseugenol B, from Litsea costalis: an in vitro study. OncoTargets Ther.10, 277–294. 10.2147/OTT.S102894

  • CrossRef
  • Google Scholar

• 2

  Afzal S. Abdul Manap A. S. Attiq A. Albokhadaim I. Kandeel M. Alhojaily S. M. (2023). From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration. Front. Pharmacol.14, 1269581. 10.3389/fphar.2023.1269581

  • CrossRef
  • Google Scholar

• 3

  Aghajanpour M. Nazer M. R. Obeidavi Z. Akbari M. Ezati P. Kor N. M. (2017). Functional foods and their role in cancer prevention and health promotion: a comprehensive review. Am. J. cancer Res.7, 740–769.

  • Google Scholar

• 4

  Agrotis A. von Chamier L. Oliver H. Kiso K. Singh T. Ketteler R. (2019). Human ATG4 autophagy proteases counteract attachment of ubiquitin-like LC3/GABARAP proteins to other cellular proteins. J. Biol. Chem.294, 12610–12621. 10.1074/jbc.AC119.009977

  • CrossRef
  • Google Scholar

• 5

  Ahmed M. B. Islam S. U. Alghamdi A. A. A. Kamran M. Ahsan H. Lee Y. S. (2022). Phytochemicals as chemo-preventive agents and signaling molecule modulators: current role in cancer therapeutics and inflammation. Int. J. Mol. Sci.23 (24), 15765. 10.3390/ijms232415765

  • CrossRef
  • Google Scholar

• 6

  Akhtar N. Baig M. W. Haq I.-U. Rajeeve V. Cutillas P. R. (2020). Withanolide metabolites inhibit PI3K/AKT and MAPK pro-survival pathways and induce apoptosis in acute myeloid leukemia cells. Biomedicines8, 333. 10.3390/biomedicines8090333

  • CrossRef
  • Google Scholar

• 7

  Albert-Gascó H. Ros-Bernal F. Castillo-Gómez E. Olucha-Bordonau F. E. (2020). MAP/ERK signaling in developing cognitive and emotional function and its effect on pathological and neurodegenerative processes. Int. J. Mol. Sci.21, 4471. 10.3390/ijms21124471

  • CrossRef
  • Google Scholar

• 8

  Almatroodi S. A. Almatroudi A. Alsahli M. A. Khan A. A. Rahmani A. H. (2020). Thymoquinone, an active compound of nigella sativa: role in prevention and treatment of cancer. Curr. Pharm. Biotechnol.21, 1028–1041. 10.2174/1389201021666200416092743

  • CrossRef
  • Google Scholar

• 9

  Almatroodi S. A. Almatroudi A. Khan A. A. Rahmani A. H. (2023). Potential therapeutic targets of formononetin, a type of methoxylated isoflavone, and its role in cancer therapy through the modulation of signal transduction pathways. Int. J. Mol. Sci.24, 9719. 10.3390/ijms24119719

  • CrossRef
  • Google Scholar

• 10

  Asgharian P. Tazekand A. P. Hosseini K. Forouhandeh H. Ghasemnejad T. Ranjbar M. et al (2022). Potential mechanisms of quercetin in cancer prevention: focus on cellular and molecular targets. Cancer Cell Int.22, 257. 10.1186/s12935-022-02677-w

  • CrossRef
  • Google Scholar

• 11

  Ashikawa K. Majumdar S. Banerjee S. Bharti A. C. Shishodia S. Aggarwal B. B. (2002). Piceatannol inhibits TNF-induced NF-kappaB activation and NF-kappaB-mediated gene expression through suppression of IkappaBalpha kinase and p65 phosphorylation. J. Immunol.169, 6490–6497. 10.4049/jimmunol.169.11.6490

  • CrossRef
  • Google Scholar

• 12

  Asih P. R. Prikas E. Stefanoska K. Tan A. R. P. Ahel H. I. Ittner A. (2020). Functions of p38 MAP kinases in the central nervous system. Front. Mol. Neurosci.13, 570586. 10.3389/fnmol.2020.570586

  • CrossRef
  • Google Scholar

• 13

  Azios N. G. Krishnamoorthy L. Harris M. Cubano L. A. Cammer M. Dharmawardhane S. F. (2007). Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. Neoplasia (New York, N.Y.)9, 147–158. 10.1593/neo.06778

  • CrossRef
  • Google Scholar

• 14

  Bai Y. Chen J. Hu W. Wang L. Wu Y. Yu S. (2022). Silibinin therapy improves cholangiocarcinoma outcomes by regulating ERK/mitochondrial pathway. Front. Pharmacol.13, 847905. 10.3389/fphar.2022.847905

  • CrossRef
  • Google Scholar

• 15

  Bakrim S. El Omari N. El Hachlafi N. Bakri Y. Lee L.-H. Bouyahya A. (2022). Dietary phenolic compounds as anticancer natural drugs: recent update on molecular mechanisms and clinical trials. Foods11, 3323. 10.3390/foods11213323

  • CrossRef
  • Google Scholar

• 16

  Balaji C. Muthukumaran J. Nalini N. (2014). Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis. Hum. Exp. Toxicol.33, 1253–1268. 10.1177/0960327114522501

  • CrossRef
  • Google Scholar

• 17

  Balakrishna P. George S. Hatoum H. Mukherjee S. (2021). Serotonin pathway in cancer. Int. J. Mol. Sci.22, 1268. 10.3390/ijms22031268

  • CrossRef
  • Google Scholar

• 18

  Bhat S. S. Prasad S. K. Shivamallu C. Prasad K. S. Syed A. Reddy P. et al (2021). Genistein: a potent anti-breast cancer agent. Curr. issues Mol. Biol.43, 1502–1517. 10.3390/cimb43030106

  • CrossRef
  • Google Scholar

• 19

  Bispo J. A. B. Pinheiro P. S. Kobetz E. K. (2020). Epidemiology and etiology of leukemia and lymphoma. Cold Spring Harb. Perspect. Med.10, a034819. 10.1101/cshperspect.a034819

  • CrossRef
  • Google Scholar

• 20

  Biswas P. Dey D. Biswas P. K. Rahaman T. I. Saha S. Parvez A. et al (2022). A comprehensive analysis and anti-cancer activities of quercetin in ROS-mediated cancer and cancer stem cells. Int. J. Mol. Sci.23, 11746. 10.3390/ijms231911746

  • CrossRef
  • Google Scholar

• 21

  Borges G. A. Elias S. T. Amorim B. de Lima C. L. Coletta R. D. Castilho R. M. et al (2020). Curcumin downregulates the PI3K-AKT-mTOR pathway and inhibits growth and progression in head and neck cancer cells. Phytotherapy Res.34, 3311–3324. 10.1002/ptr.6780

  • CrossRef
  • Google Scholar

• 22

  Brouckaert G. Kalai M. Krysko D. V. Saelens X. Vercammen D. Ndlovu M. N. et al (2004). Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol. Biol. Cell15, 1089–1100. 10.1091/mbc.e03-09-0668

  • CrossRef
  • Google Scholar

• 23

  Brown J. S. Amend S. R. Austin R. H. Gatenby R. A. Hammarlund E. U. Pienta K. J. (2023). Updating the definition of cancer. Mol. cancer Res. MCR21, 1142–1147. 10.1158/1541-7786.MCR-23-0411

  • CrossRef
  • Google Scholar

• 24

  Buhrmann C. Yazdi M. Popper B. Shayan P. Goel A. Aggarwal B. B. et al (2019). Evidence that TNF-β induces proliferation in colorectal cancer cells and resveratrol can down-modulate it. Exp. Biol. Med. (Maywood, N.J.)244, 1–12. 10.1177/1535370218824538

  • CrossRef
  • Google Scholar

• 25

  Burdusel A. C. Gherasim O. Grumezescu A. Mogoantă L. Ficai A. Andronescu E. (2018). Biomedical applications of silver nanoparticles: an up-to-date overview. Nanomaterials8, 681. 10.3390/nano8090681

  • CrossRef
  • Google Scholar

• 26

  Cargnello M. Roux P. P. (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev.75, 50–83. 10.1128/MMBR.00031-10

  • CrossRef
  • Google Scholar

• 27

  Chan L.-P. Chou T.-H. Ding H.-Y. Chen P.-R. Chiang F.-Y. Kuo P.-L. et al (2012). Apigenin induces apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin. Biochimica biophysica acta1820, 1081–1091. 10.1016/j.bbagen.2012.04.013

  • CrossRef
  • Google Scholar

• 28

  Chang C.-I. Chien W.-C. Huang K.-X. Hsu J.-L. (2017). Anti-inflammatory effects of vitisinol A and four other oligostilbenes from ampelopsis brevipedunculata var. Hancei. Molecules22, 1195. 10.3390/molecules22071195

  • CrossRef
  • Google Scholar

• 29

  Chang Y. J. Hsu S. L. Liu Y. T. Lin Y. H. Lin M. H. Huang S. J. et al (2015). Gallic acid induces necroptosis via TNF-α signaling pathway in activated hepatic stellate cells. PloS one10, e0120713. 10.1371/journal.pone.0120713

  • CrossRef
  • Google Scholar

• 30

  Chao J.-I. Su W.-C. Liu H.-F. (2007). Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. Mol. cancer Ther.6, 3039–3048. 10.1158/1535-7163.MCT-07-0281

  • CrossRef
  • Google Scholar

• 31

  Chebet J. J. Ehiri J. E. McClelland D. J. Taren D. Hakim I. A. (2021). Effect of d-limonene and its derivatives on breast cancer in human trials: a scoping review and narrative synthesis. BMC cancer21, 902. 10.1186/s12885-021-08639-1

  • CrossRef
  • Google Scholar

• 32

  Chen J. (2016). The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med.6, a026104. 10.1101/cshperspect.a026104

  • CrossRef
  • Google Scholar

• 33

  Chen J. Ye C. Wan C. Li G. Peng L. Peng Y. et al (2021). The roles of c-jun N-terminal kinase (JNK) in infectious diseases. Int. J. Mol. Sci.22, 9640. 10.3390/ijms22179640

  • CrossRef
  • Google Scholar

• 34

  Chen J.-C. Wu C.-H. Peng Y.-S. Zheng H.-Y. Lin Y.-C. Ma P.-F. et al (2018). Astaxanthin enhances erlotinib-induced cytotoxicity by p38 MAPK mediated xeroderma pigmentosum complementation group C (XPC) down-regulation in human lung cancer cells. Toxicol. Res.7, 1247–1256. 10.1039/c7tx00292k

  • CrossRef
  • Google Scholar

• 35

  Chen K. Zhang S. Ji Y. Li J. An P. Ren H. et al (2013b). Baicalein inhibits the invasion and metastatic capabilities of hepatocellular carcinoma cells via down-regulation of the ERK pathway. PloS one8, e72927. 10.1371/journal.pone.0072927

  • CrossRef
  • Google Scholar

• 36

  Chen K.-C. Chen C.-Y. Lin C.-R. Yang T.-Y. Chen T.-H. Wu L.-C. et al (2013a). Luteolin attenuates TGF-β1-induced epithelial-mesenchymal transition of lung cancer cells by interfering in the PI3K/Akt-NF-κB-Snail pathway. Life Sci.93, 924–933. 10.1016/j.lfs.2013.10.004

  • CrossRef
  • Google Scholar

• 37

  Chen Q. Zheng Y. Jiao D. Chen F. Hu H. Wu Y. et al (2014a). Curcumin inhibits lung cancer cell migration and invasion through Rac1-dependent signaling pathway. J. Nutr. Biochem.25, 177–185. 10.1016/j.jnutbio.2013.10.004

  • CrossRef
  • Google Scholar

• 38

  Chen S. Wang Z. Huang Y. O’Barr S. A. Wong R. A. Yeung S. et al (2014b). Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review. Evidence-based complementary Altern. Med.2014, 168940. 10.1155/2014/168940

  • CrossRef
  • Google Scholar

• 39

  Cheng A.-W. Tan X. Sun J.-Y. Gu C.-M. Liu C. Guo X. (2019). Catechin attenuates TNF-α induced inflammatory response via AMPK-SIRT1 pathway in 3T3-L1 adipocytes. PloS one14, e0217090. 10.1371/journal.pone.0217090

  • CrossRef
  • Google Scholar

• 40

  Cheng L. Xia F. Li Z. Shen C. Yang Z. Hou H. et al (2023). Structure, function and drug discovery of GPCR signaling. Mol. Biomed.4, 46. 10.1186/s43556-023-00156-w

  • CrossRef
  • Google Scholar

• 41

  Cheon C. Ko S.-G. (2022). Synergistic effects of natural products in combination with anticancer agents in prostate cancer: a scoping review. Front. Pharmacol.13, 963317. 10.3389/fphar.2022.963317

  • CrossRef
  • Google Scholar

• 42

  Choudhari A. S. Mandave P. C. Deshpande M. Ranjekar P. Prakash O. (2019). Phytochemicals in cancer treatment: from preclinical studies to clinical practice. Front. Pharmacol.10, 1614. 10.3389/fphar.2019.01614

  • CrossRef
  • Google Scholar

• 43

  Chung K.-S. Choi J.-H. Back N.-I. Choi M.-S. Kang E.-K. Chung H.-G. et al (2010). Eupafolin, a flavonoid isolated from Artemisia princeps, induced apoptosis in human cervical adenocarcinoma HeLa cells. Mol. Nutr. food Res.54, 1318–1328. 10.1002/mnfr.200900305

  • CrossRef
  • Google Scholar

• 44

  Collins H. M. Abdelghany M. K. Messmer M. Yue B. Deeves S. E. Kindle K. B. et al (2013). Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells. BMC cancer13, 37. 10.1186/1471-2407-13-37

  • CrossRef
  • Google Scholar

• 45

  Cruz M. A. A. S. Coimbra P. P. S. Araújo-Lima C. F. Freitas-Silva O. Teodoro A. J. (2024). Hybrid fruits for improving health-A comprehensive review. Foods13, 219. 10.3390/foods13020219

  • CrossRef
  • Google Scholar

• 46

  Cui J. Li X. Wang S. Su Y. Chen X. Cao L. et al (2020). Triptolide prevents bone loss via suppressing osteoclastogenesis through inhibiting PI3K-AKT-NFATc1 pathway. J. Cell. Mol. Med.24, 6149–6161. 10.1111/jcmm.15229

  • CrossRef
  • Google Scholar

• 47

  Dai Q. Franke A. A. Jin F. Shu X.-O. Hebert J. R. Custer L. J. et al (2002). Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai. Cancer Epidemiol. biomarkers Prev.11, 815–821.

  • Google Scholar

• 48

  Dembitsky V. M. Gloriozova T. A. Poroikov V. V. (2021). Antitumor profile of carbon-bridged steroids (CBS) and triterpenoids. Mar. drugs19, 324. 10.3390/md19060324

  • CrossRef
  • Google Scholar

• 49

  Dhokia V. Moss J. A. Y. Macip S. Fox J. L. (2022). At the crossroads of life and death: the proteins that influence cell fate decisions. Cancers14, 2745. 10.3390/cancers14112745

  • CrossRef
  • Google Scholar

• 50

  Dhyani P. Quispe C. Sharma E. Bahukhandi A. Sati P. Attri D. C. et al (2022). Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell Int.22, 206. 10.1186/s12935-022-02624-9

  • CrossRef
  • Google Scholar

• 51

  Djavan B. Nasu Y. (2001). Prostate cancer gene therapy-what have we learned and where are we going?Rev. urology3, 179–186.

  • Google Scholar

• 52

  Dos Santos M. B. Bertholin Anselmo D. de Oliveira J. G. Jardim-Perassi B. V. Alves Monteiro D. Silva G. et al (2019). Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells. J. enzyme inhibition Med. Chem.34, 1093–1099. 10.1080/14756366.2019.1615485

  • CrossRef
  • Google Scholar

• 53

  Dowling J. J. Weihl C. C. Spencer M. J. (2021). Molecular and cellular basis of genetically inherited skeletal muscle disorders. Nat. Rev. Mol. Cell Biol.22, 713–732. 10.1038/s41580-021-00389-z

  • CrossRef
  • Google Scholar

• 54

  Duan W.-J. Li Q.-S. Xia M.-Y. Tashiro S.-I. Onodera S. Ikejima T. (2011). Silibinin activated ROS-p38-NF-κB positive feedback and induced autophagic death in human fibrosarcoma HT1080 cells. J. Asian Nat. Prod. Res.13, 27–35. 10.1080/10286020.2010.540757

  • CrossRef
  • Google Scholar

• 55

  Efferth T. Saeed M. E. M. Mirghani E. Alim A. Yassin Z. Saeed E. et al (2017). Integration of phytochemicals and phytotherapy into cancer precision medicine. Oncotarget8, 50284–50304. 10.18632/oncotarget.17466

  • CrossRef
  • Google Scholar

• 56

  Elekofehinti O. O. Iwaloye O. Olawale F. Ariyo E. O. (2021). Saponins in cancer treatment: current progress and future prospects. Pathophysiol. official J. Int. Soc. Pathophysiol.28, 250–272. 10.3390/pathophysiology28020017

  • CrossRef
  • Google Scholar

• 57

  Elmore S. (2007). Apoptosis: a review of programmed cell death. Toxicol. Pathol.35, 495–516. 10.1080/01926230701320337

  • CrossRef
  • Google Scholar

• 58

  Evangelatos G. Bamias G. Kitas G. D. Kollias G. Sfikakis P. P. (2022). The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era. Rheumatol. Int.42, 1493–1511. 10.1007/s00296-022-05136-x

  • CrossRef
  • Google Scholar

• 59

  Falcicchia C. Tozzi F. Arancio O. Watterson D. M. Origlia N. (2020). Involvement of p38 MAPK in synaptic function and dysfunction. Int. J. Mol. Sci.21, 5624. 10.3390/ijms21165624

  • CrossRef
  • Google Scholar

• 60

  Fawaz A. Ferraresi A. Isidoro C. (2023). Systems biology in cancer diagnosis integrating omics technologies and artificial intelligence to support physician decision making. J. personalized Med.13, 1590. 10.3390/jpm13111590

  • CrossRef
  • Google Scholar

• 61

  Fu H. Wang C. Yang D. Wei Z. Xu J. Hu Z. et al (2018). Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling. J. Cell. physiology233, 4634–4642. 10.1002/jcp.26190

  • CrossRef
  • Google Scholar

• 62

  G M. S. Swetha M. Keerthana C. K. Rayginia T. P. Anto R. J. (2021). Cancer chemoprevention: a strategic approach using phytochemicals. Front. Pharmacol.12, 809308. 10.3389/fphar.2021.809308

  • CrossRef
  • Google Scholar

• 63

  Gan D. He W. Yin H. Gou X. (2020). β-elemene enhances cisplatin-induced apoptosis in bladder cancer cells through the ROS-AMPK signaling pathway. Oncol. Lett.19, 291–300. 10.3892/ol.2019.11103

  • CrossRef
  • Google Scholar

• 64

  Ganguly P. Macleod T. Wong C. Harland M. McGonagle D. (2023). Revisiting p38 mitogen-activated protein kinases (MAPK) in inflammatory arthritis: a narrative of the emergence of MAPK-activated protein kinase inhibitors (MK2i). Pharm. (Basel)16, 1286. 10.3390/ph16091286

  • CrossRef
  • Google Scholar

• 65

  Gao Y. Yin J. Rankin G. O. Chen Y. C. (2018). Kaempferol induces G2/M cell cycle arrest via checkpoint kinase 2 and promotes apoptosis via death receptors in human ovarian carcinoma A2780/CP70 cells. Molecules23, 1095. 10.3390/molecules23051095

  • CrossRef
  • Google Scholar

• 66

  George B. P. Chandran R. Abrahamse H. (2021). Role of phytochemicals in cancer chemoprevention: insights. Antioxidants (Basel)10, 1455. 10.3390/antiox10091455

  • CrossRef
  • Google Scholar

• 67

  Gnesutta N. Minden A. (2003). Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol. Cell. Biol.23, 7838–7848. 10.1128/MCB.23.21.7838-7848.2003

  • CrossRef
  • Google Scholar

• 68

  Gómez-Virgilio L. Silva-Lucero M.-D.-C. Flores-Morelos D.-S. Gallardo-Nieto J. Lopez-Toledo G. Abarca-Fernandez A.-M. et al (2022). Autophagy: a key regulator of homeostasis and disease: an overview of molecular mechanisms and modulators. Cells11, 2262. 10.3390/cells11152262

  • CrossRef
  • Google Scholar

• 69

  Granado-Serrano A. B. Martín M. Á. Bravo L. Goya L. Ramos S. (2012). Quercetin attenuates TNF-induced inflammation in hepatic cells by inhibiting the NF-κB pathway. Nutr. cancer64, 588–598. 10.1080/01635581.2012.661513

  • CrossRef
  • Google Scholar

• 70

  Green D. R. (2022). The death receptor pathway of apoptosis. Cold Spring Harb. Perspect. Biol.14, a041053. 10.1101/cshperspect.a041053

  • CrossRef
  • Google Scholar

• 71

  Guillamón E. Mut-Salud N. Rodríguez-Sojo M. J. Ruiz-Malagón A. J. Cuberos-Escobar A. Martínez-Férez A. et al (2023). In vitro antitumor and anti-inflammatory activities of allium-derived compounds propyl propane thiosulfonate (PTSO) and propyl propane thiosulfinate (PTS). Nutrients15, 1363. 10.3390/nu15061363

  • CrossRef
  • Google Scholar

• 72

  Gulati N. Laudet B. Zohrabian V. M. Murali R. Jhanwar-Uniyal M. (2006). The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res.26, 1177–1181.

  • Google Scholar

• 73

  Guo Y.-B. Bao X.-J. Xu S.-B. Zhang X.-D. Liu H.-Y. (2015). Honokiol induces cell cycle arrest and apoptosis via p53 activation in H4 human neuroglioma cells. Int. J. Clin. Exp. Med.8, 7168–7175.

  • Google Scholar

• 74

  Gupta S. C. Patchva S. Koh W. Aggarwal B. B. (2012). Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin. Exp. Pharmacol. physiology39, 283–299. 10.1111/j.1440-1681.2011.05648.x

  • CrossRef
  • Google Scholar

• 75

  Gv V. Ranganathan P. J. Palati S. (2023). Tangeretin’s anti-apoptotic signaling mechanisms in oral cancer cells: in vitro anti-cancer activity. Cureus15, e47452. 10.7759/cureus.47452

  • CrossRef
  • Google Scholar

• 76

  Hafeez B. B. Mustafa A. Fischer J. W. Singh A. Zhong W. Shekhani M. O. et al (2014). α-Mangostin: a dietary antioxidant derived from the pericarp of Garcinia mangostana L. inhibits pancreatic tumor growth in xenograft mouse model. Antioxidants redox Signal.21, 682–699. 10.1089/ars.2013.5212

  • CrossRef
  • Google Scholar

• 77

  Hehlgans T. Pfeffer K. (2005). The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology115, 1–20. 10.1111/j.1365-2567.2005.02143.x

  • CrossRef
  • Google Scholar

• 78

  Ho J. F. V. Yaakup H. Low G. S. H. Wong S. L. Tho L. M. Tan S. B. (2020). Morphine use for cancer pain: a strong analgesic used only at the end of life? A qualitative study on attitudes and perceptions of morphine in patients with advanced cancer and their caregivers. Palliat. Med.34, 619–629. 10.1177/0269216320904905

  • CrossRef
  • Google Scholar

• 79

  Hoffmann J. C. Pappa A. Krammer P. H. Lavrik I. N. (2009). A new C-terminal cleavage product of procaspase-8, p30, defines an alternative pathway of procaspase-8 activation. Mol. Cell. Biol.29, 4431–4440. 10.1128/MCB.02261-07

  • CrossRef
  • Google Scholar

• 80

  Hong T.-K. Song J.-H. Lee S.-B. Do J.-T. (2021). Germ cell derivation from pluripotent stem cells for understanding in vitro gametogenesis. Cells10, 1889. 10.3390/cells10081889

  • CrossRef
  • Google Scholar

• 81

  Hu C. He Y. (2021). Formononetin inhibits non-small cell lung cancer proliferation via regulation of mir-27a-3p through p53 pathway. Oncologie23, 241–250. 10.32604/Oncologie.2021.015828

  • CrossRef
  • Google Scholar

• 82

  Hu Y. Reggiori F. (2022). Molecular regulation of autophagosome formation. Biochem. Soc. Trans.50, 55–69. 10.1042/BST20210819

  • CrossRef
  • Google Scholar

• 83

  Huang Y. Wang G. Zhang N. Zeng X. (2024). MAP3K4 kinase action and dual role in cancer. Discov. Oncol.15, 99. 10.1007/s12672-024-00961-x

  • CrossRef
  • Google Scholar

• 84

  Hun Lee J. Shu L. Fuentes F. Su Z.-Y. Tony Kong A.-N. (2013). Cancer chemoprevention by traditional Chinese herbal medicine and dietary phytochemicals: targeting nrf2-mediated oxidative stress/anti-inflammatory responses, epigenetics, and cancer stem cells. J. traditional complementary Med.3, 69–79. 10.4103/2225-4110.107700

  • CrossRef
  • Google Scholar

• 85

  Hussain Y. Cui J. H. Khan H. Aschner M. Batiha G. E.-S. Jeandet P. (2021). Luteolin and cancer metastasis suppression: focus on the role of epithelial to mesenchymal transition. Med. Oncol. N. Lond. Engl.38, 66. 10.1007/s12032-021-01508-8

  • CrossRef
  • Google Scholar

• 86

  Ilyas S. Simanullang R. H. Hutahaean S. Rosidah R. Situmorang P. C. (2021). Effect of Zanthoxylum acanthopodium methanol extract on CDK4 expression to cervical cancer. Res. J Pharm. Technol.14 (11), 5647–5652. 10.52711/0974-360X.2021.00982

  • CrossRef
  • Google Scholar

• 87

  Ilyas S. Simanullang R. H. Hutahaean S. Rosidah R. Situmorang P. C. (2022). Correlation of myc expression with Wee1 expression by Zanthoxylum acanthopodium in cervical carcinoma histology. Pak J. Biol. Sci.25 (11), 1014–1020. 10.3923/pjbs.2022.1014.1020

  • CrossRef
  • Google Scholar

• 88

  Imai-Sumida M. Chiyomaru T. Majid S. Saini S. Nip H. Dahiya R. et al (2017). Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways. Oncotarget8, 92032–92042. 10.18632/oncotarget.20734

  • CrossRef
  • Google Scholar

• 89

  Irianti E. Ilyas S. Hutahaean S. Rosidah Situmorang P. C. (2020). Placental histological on preeclamptic rats (Rattus norvegicus) after administration of nanoherbal haramonting (Rhodomyrtus tomentosa). Res. J. Pharm. Tech.13 (8), 3879–3882. 10.5958/0974-360X.2020.00686.1

  • CrossRef
  • Google Scholar

• 90

  Jang J. H. Yang E. S. Min K.-J. Kwon T. K. (2012). Inhibitory effect of butein on tumor necrosis factor-α-induced expression of cell adhesion molecules in human lung epithelial cells via inhibition of reactive oxygen species generation, NF-κB activation and Akt phosphorylation. Int. J. Mol. Med.30, 1357–1364. 10.3892/ijmm.2012.1158

  • CrossRef
  • Google Scholar

• 91

  Jang J. Y. Im E. Kim N. D. (2022). Mechanism of resveratrol-induced programmed cell death and new drug discovery against cancer: a review. Int. J. Mol. Sci.23, 13689. 10.3390/ijms232213689

  • CrossRef
  • Google Scholar

• 92

  Jeong J.-H. Nakajima H. Magae J. Furukawa C. Taki K. Otsuka K. et al (2009). Ascochlorin activates p53 in a manner distinct from DNA damaging agents. Int. J. cancer124, 2797–2803. 10.1002/ijc.24259

  • CrossRef
  • Google Scholar

• 93

  Jia S. Xu X. Zhou S. Chen Y. Ding G. Cao L. (2019). Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell death Dis.10, 142. 10.1038/s41419-019-1366-y

  • CrossRef
  • Google Scholar

• 94

  Jin X. Che D.-B. Zhang Z.-H. Yan H.-M. Jia Z.-Y. Jia X.-B. (2016). Ginseng consumption and risk of cancer: a meta-analysis. J. ginseng Res.40, 269–277. 10.1016/j.jgr.2015.08.007

  • CrossRef
  • Google Scholar

• 95

  Jo J. Abdi Nansa S. Kim D.-H. (2020). Molecular regulators of cellular mechanoadaptation at cell-material interfaces. Front. Bioeng. Biotechnol.8, 608569. 10.3389/fbioe.2020.608569

  • CrossRef
  • Google Scholar

• 96

  Johnson R. Dludla P. V. Muller C. J. F. Huisamen B. Essop M. F. Louw J. (2017). The transcription profile unveils the cardioprotective effect of aspalathin against lipid toxicity in an in vitro H9c2 model. Molecules22, 219. 10.3390/molecules22020219

  • CrossRef
  • Google Scholar

• 97

  Jung J. E. Kim H. S. Lee C. S. Park D.-H. Kim Y.-N. Lee M.-J. et al (2007). Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. Carcinogenesis28, 1780–1787. 10.1093/carcin/bgm130

  • CrossRef
  • Google Scholar

• 98

  Kang S. H. Bak D.-H. Chung B. Y. Bai H.-W. Kang B. S. (2020). Delphinidin enhances radio-therapeutic effects via autophagy induction and JNK/MAPK pathway activation in non-small cell lung cancer. Korean J. physiology Pharmacol.24, 413–422. 10.4196/kjpp.2020.24.5.413

  • CrossRef
  • Google Scholar

• 99

  Kanwal N. Rasul A. Hussain G. Anwar H. Shah M. A. Sarfraz I. et al (2020). Oleandrin: a bioactive phytochemical and potential cancer killer via multiple cellular signaling pathways. Food Chem. Toxicol.143, 111570. 10.1016/j.fct.2020.111570

  • CrossRef
  • Google Scholar

• 100

  Kashafi E. Moradzadeh M. Mohamadkhani A. Erfanian S. (2017). Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed. Pharmacother.89, 573–577. 10.1016/j.biopha.2017.02.061

  • CrossRef
  • Google Scholar

• 101

  Kast R. E. (2003). Ribavirin in cancer immunotherapies: controlling nitric oxide augments cytotoxic lymphocyte function. Neoplasia (New York, N.Y.)5, 3–8. 10.1016/s1476-5586(03)80011-8

  • CrossRef
  • Google Scholar

• 102

  Kavitha K. Kowshik J. Kishore T. K. K. Baba A. B. Nagini S. (2013). Astaxanthin inhibits NF-κB and Wnt/β-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer. Biochimica biophysica acta1830, 4433–4444. 10.1016/j.bbagen.2013.05.032

  • CrossRef
  • Google Scholar

• 103

  Kciuk M. Alam M. Ali N. Rashid S. Głowacka P. Sundaraj R. et al (2023). Epigallocatechin-3-Gallate therapeutic potential in cancer: mechanism of action and clinical implications. Molecules28, 5246. 10.3390/molecules28135246

  • CrossRef
  • Google Scholar

• 104

  Kciuk M. Gielecińska A. Budzinska A. Mojzych M. Kontek R. (2022). Metastasis and MAPK pathways. Int. J. Mol. Sci.23, 3847. 10.3390/ijms23073847

  • CrossRef
  • Google Scholar

• 105

  Khafaga D. S. R. El-Khawaga A. M. Elfattah Mohammed R. A. Abdelhakim H. K. (2023). Green synthesis of nano-based drug delivery systems developed for hepatocellular carcinoma treatment: a review. Mol. Biol. Rep.50, 10351–10364. 10.1007/s11033-023-08823-5

  • CrossRef
  • Google Scholar

• 106

  Kikuchi H. Yuan B. Yuhara E. Takagi N. Toyoda H. (2013). Involvement of histone H3 phosphorylation through p38 MAPK pathway activation in casticin-induced cytocidal effects against the human promyelocytic cell line HL-60. Int. J. Oncol.43, 2046–2056. 10.3892/ijo.2013.2106

  • CrossRef
  • Google Scholar

• 107

  Kim H. Lee M.-J. Kim J.-E. Park S.-D. Moon H.-I. Park W.-H. (2010). Genistein suppresses tumor necrosis factor-alpha-induced proliferation via the apoptotic signaling pathway in human aortic smooth muscle cells. J. Agric. food Chem.58, 2015–2019. 10.1021/jf903802v

  • CrossRef
  • Google Scholar

• 108

  Kim H.-J. Hwang K.-E. Park D.-S. Oh S.-H. Jun H. Y. Yoon K.-H. et al (2017). Shikonin-induced necroptosis is enhanced by the inhibition of autophagy in non-small cell lung cancer cells. J. Transl. Med.15, 123. 10.1186/s12967-017-1223-7

  • CrossRef
  • Google Scholar

• 109

  Kim M. E. Na J. Y. Lee J. S. (2018). Anti-inflammatory effects of trans-cinnamaldehyde on lipopolysaccharide-stimulated macrophage activation via MAPKs pathway regulation. Immunopharmacol. Immunotoxicol.40, 219–224. 10.1080/08923973.2018.1424902

  • CrossRef
  • Google Scholar

• 110

  Kim M. S. Kang H. J. Moon A. (2001). Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Archives pharmacal Res.24, 349–354. 10.1007/BF02975105

  • CrossRef
  • Google Scholar

• 111

  Kim N. Chung G. Son S.-R. Park J. H. Lee Y. H. Park K.-T. et al (2023). Magnolin inhibits paclitaxel-induced cold allodynia and ERK1/2 activation in mice. Plants12, 2283. 10.3390/plants12122283

  • CrossRef
  • Google Scholar

• 112

  King S. J. Worth D. C. Scales T. M. E. Monypenny J. Jones G. E. Parsons M. (2011). β1 integrins regulate fibroblast chemotaxis through control of N-WASP stability. EMBO J.30, 1705–1718. 10.1038/emboj.2011.82

  • CrossRef
  • Google Scholar

• 113

  Kłósek M. Mertas A. Król W. Jaworska D. Szymszal J. Szliszka E. (2016). Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells after treatment with xanthohumol-A natural compound present in humulus lupulus L. Int. J. Mol. Sci.17, 837. 10.3390/ijms17060837

  • CrossRef
  • Google Scholar

• 114

  Ko A. M.-S. Tu H.-P. Ko Y.-C. (2023). Systematic review of roles of arecoline and arecoline N-oxide in oral cancer and strategies to block carcinogenesis. Cells12, 1208. 10.3390/cells12081208

  • CrossRef
  • Google Scholar

• 115

  Kou Y. Tong B. Wu W. Liao X. Zhao M. (2020). Berberine improves chemo-sensitivity to cisplatin by enhancing cell apoptosis and repressing PI3K/AKT/mTOR signaling pathway in gastric cancer. Front. Pharmacol.11, 616251. 10.3389/fphar.2020.616251

  • CrossRef
  • Google Scholar

• 116

  Koul H. K. Pal M. Koul S. (2013). Role of p38 MAP kinase signal transduction in solid tumors. Genes & cancer4, 342–359. 10.1177/1947601913507951

  • CrossRef
  • Google Scholar

• 117

  Kretschmer N. Rinner B. Stuendl N. Kaltenegger H. Wolf E. Kunert O. et al (2012). Effect of costunolide and dehydrocostus lactone on cell cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta medica. 78, 1749–1756. 10.1055/s-0032-1315385

  • CrossRef
  • Google Scholar

• 118

  Kurniasih N. Supriadin A. Harneti D. Abdulah R. Azmi M. Supratman U. (2021). Ergosterol peroxide and stigmasterol from the stembark of aglaia simplicifolia (meliaceae) and their cytotoxic against HeLa cervical cancer cell lines. J. Kim. Val.1, 46–51. 10.15408/jkv.v1i1.20068

  • CrossRef
  • Google Scholar

• 119

  Kwon O. S. Jung J. H. Shin E. A. Park J. E. Park W. Y. Kim S.-H. (2020). Epigallocatechin-3-Gallate induces apoptosis as a TRAIL sensitizer via activation of caspase 8 and death receptor 5 in human colon cancer cells. Biomedicines8, 84. 10.3390/biomedicines8040084

  • CrossRef
  • Google Scholar

• 120

  Lecomte N. Njardarson J. T. Nagorny P. Yang G. Downey R. Ouerfelli O. et al (2011). Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin. Proc. Natl. Acad. Sci. U. S. A.108, 15074–15078. 10.1073/pnas.1015247108

  • CrossRef
  • Google Scholar

• 121

  Lee C.-H. Ying T.-H. Chiou H.-L. Hsieh S.-C. Wen S.-H. Chou R.-H. et al (2017). Alpha-mangostin induces apoptosis through activation of reactive oxygen species and ASK1/p38 signaling pathway in cervical cancer cells. Oncotarget8, 47425–47439. 10.18632/oncotarget.17659

  • CrossRef
  • Google Scholar

• 122

  Lee D.-Y. Yun S.-M. Song M.-Y. Jung K. Kim E.-H. (2020a). Cyanidin chloride induces apoptosis by inhibiting NF-κB signaling through activation of Nrf2 in colorectal cancer cells. Antioxidants (Basel)9, 285. 10.3390/antiox9040285

  • CrossRef
  • Google Scholar

• 123

  Lee H.-P. Li T.-M. Tsao J.-Y. Fong Y.-C. Tang C.-H. (2012). Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway. Int. Immunopharmacol.13, 163–169. 10.1016/j.intimp.2012.04.002

  • CrossRef
  • Google Scholar

• 124

  Lee M.-G. Lee K.-S. Nam K.-S. (2020b). Anti-metastatic effects of arctigenin are regulated by MAPK/AP-1 signaling in 4T-1 mouse breast cancer cells. Mol. Med. Rep.21, 1374–1382. 10.3892/mmr.2020.10937

  • CrossRef
  • Google Scholar

• 125

  Lee M.-S. Yuet-Wa J. C. Kong S.-K. Yu B. Eng-Choon V. O. Nai-Ching H. W. et al (2005). Effects of polyphyllin D, a steroidal saponin in Paris polyphylla, in growth inhibition of human breast cancer cells and in xenograft. Cancer Biol. Ther.4, 1248–1254. 10.4161/cbt.4.11.2136

  • CrossRef
  • Google Scholar

• 126

  Li C. Yang X. Chen C. Cai S. Hu J. (2014). Isorhamnetin suppresses colon cancer cell growth through the PI3K-Akt-mTOR pathway. Mol. Med. Rep.9, 935–940. 10.3892/mmr.2014.1886

  • CrossRef
  • Google Scholar

• 127

  Li D. Wang G. Jin G. Yao K. Zhao Z. Bie L. et al (2019). Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int. J. Mol. Med.43, 630–640. 10.3892/ijmm.2018.3969

  • CrossRef
  • Google Scholar

• 128

  Li H. Du G. Yang L. Pang L. Zhan Y. (2020). The antitumor effects of britanin on hepatocellular carcinoma cells and its real-time evaluation by in vivo bioluminescence imaging. Anti-cancer agents Med. Chem.20, 1147–1156. 10.2174/1871520620666200227092623

  • CrossRef
  • Google Scholar

• 129

  Li M. Beg A. A. (2000). Induction of necrotic-like cell death by tumor necrosis factor alpha and caspase inhibitors: novel mechanism for killing virus-infected cells. J. virology74, 7470–7477. 10.1128/jvi.74.16.7470-7477.2000

  • CrossRef
  • Google Scholar

• 130

  Li R. Inbaraj B. S. Chen B.-H. (2023). Quantification of xanthone and anthocyanin in mangosteen peel by UPLC-MS/MS and preparation of nanoemulsions for studying their inhibition effects on liver cancer cells. Int. J. Mol. Sci.24, 3934. 10.3390/ijms24043934

  • CrossRef
  • Google Scholar

• 131

  Li S. Chen J. Fan Y. Wang C. Wang C. Zheng X. et al (2022). Liposomal Honokiol induces ROS-mediated apoptosis via regulation of ERK/p38-MAPK signaling and autophagic inhibition in human medulloblastoma. Signal Transduct. Target. Ther.7, 49. 10.1038/s41392-021-00869-w

  • CrossRef
  • Google Scholar

• 132

  Li X. Zhao J. Yan T. Mu J. Lin Y. Chen J. et al (2021). Cyanidin-3-O-glucoside and cisplatin inhibit proliferation and downregulate the PI3K/AKT/mTOR pathway in cervical cancer cells. J. food Sci.86, 2700–2712. 10.1111/1750-3841.15740

  • CrossRef
  • Google Scholar

• 133

  Liang F. Lv Y. Qiao X. Zhang S. Shen S. Wang C. et al (2023). Cinchonine-induced cell death in pancreatic cancer cells by downregulating RRP15. Cell Biol. Int.47, 907–919. 10.1002/cbin.11987

  • CrossRef
  • Google Scholar

• 134

  Liang X. Wang P. Yang C. Huang F. Wu H. Shi H. et al (2021). Galangin inhibits gastric cancer growth through enhancing STAT3 mediated ROS production. Front. Pharmacol.12, 646628. 10.3389/fphar.2021.646628

  • CrossRef
  • Google Scholar

• 135

  Lim W. Jeong M. Bazer F. W. Song G. (2016). Curcumin suppresses proliferation and migration and induces apoptosis on human placental choriocarcinoma cells via ERK1/2 and SAPK/JNK MAPK signaling pathways. Biol. reproduction95, 83. 10.1095/biolreprod.116.141630

  • CrossRef
  • Google Scholar

• 136

  Lin F.-L. Hsu J.-L. Chou C.-H. Wu W.-J. Chang C.-I. Liu H.-J. (2011). Activation of p38 MAPK by damnacanthal mediates apoptosis in SKHep 1 cells through the DR5/TRAIL and TNFR1/TNF-α and p53 pathways. Eur. J. Pharmacol.650, 120–129. 10.1016/j.ejphar.2010.10.005

  • CrossRef
  • Google Scholar

• 137

  Lin H.-F. Hsieh M.-J. Hsi Y.-T. Lo Y.-S. Chuang Y.-C. Chen M.-K. et al (2017). Celastrol-induced apoptosis in human nasopharyngeal carcinoma is associated with the activation of the death receptor and the mitochondrial pathway. Oncol. Lett.14, 1683–1690. 10.3892/ol.2017.6346

  • CrossRef
  • Google Scholar

• 138

  Liu M.-J. Wang Z. Ju Y. Wong R. N.-S. Wu Q.-Y. (2005). Diosgenin induces cell cycle arrest and apoptosis in human leukemia K562 cells with the disruption of Ca2+ homeostasis. Cancer Chemother. Pharmacol.55, 79–90. 10.1007/s00280-004-0849-3

  • CrossRef
  • Google Scholar

• 139

  Liu Q. Xu X. Zhao M. Wei Z. Li X. Zhang X. et al (2015). Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway. Mol. cancer Ther.14, 355–363. 10.1158/1535-7163.MCT-14-0634

  • CrossRef
  • Google Scholar

• 140

  Liu T. He Y. Liao Y. (2024). Anacardic acid inhibits the proliferation and inflammation of HaCaT cells induced by TNF- α via the regulation of NF - κB pathway. Trop. J. Pharm. Res.23, 251–256. 10.4314/tjpr.v23i2.3

  • CrossRef
  • Google Scholar

• 141

  Lu J.-J. Bao J.-L. Chen X.-P. Huang M. Wang Y.-T. (2012). Alkaloids isolated from natural herbs as the anticancer agents. Evidence-based complementary Altern. Med.2012, 485042. 10.1155/2012/485042

  • CrossRef
  • Google Scholar

• 142

  Łukasiewicz S. Czeczelewski M. Forma A. Baj J. Sitarz R. Stanisławek A. (2021). Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies-an updated review. Cancers13, 4287. 10.3390/cancers13174287

  • CrossRef
  • Google Scholar

• 143

  Luo K. W. Lung W. Y. Chun-Xie Luo X. L. Huang W. R. (2018). EGCG inhibited bladder cancer T24 and 5637 cell proliferation and migration via PI3K/AKT pathway. Oncotarget9, 12261–12272. 10.18632/oncotarget.24301

  • CrossRef
  • Google Scholar

• 144

  Madureira M. B. Concato V. M. Cruz E. M. S. Bitencourt de Morais J. M. Inoue F. S. R. Concimo Santos N. et al (2023). Naringenin and hesperidin as promising alternatives for prevention and Co-adjuvant therapy for breast cancer. Antioxidants (Basel)12, 586. 10.3390/antiox12030586

  • CrossRef
  • Google Scholar

• 145

  Mahmoud M. A. Okda T. M. Omran G. A. Abd-Alhaseeb M. M. (2021). Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-p53-caspase-3 pathways modulation. J. Appl. Biomed.19, 202–209. 10.32725/jab.2021.024

  • CrossRef
  • Google Scholar

• 146

  Mak T. W. Yeh W.-C. (2002). Signaling for survival and apoptosis in the immune system. Arthritis Res.4 (Suppl. 3), S243–S252. 10.1186/ar569

  • CrossRef
  • Google Scholar

• 147

  Mari A. Mani G. Nagabhishek S. N. Balaraman G. Subramanian N. Mirza F. B. et al (2021). Carvacrol promotes cell cycle arrest and apoptosis through PI3K/AKT signaling pathway in MCF-7 breast cancer cells. Chin. J. Integr. Med.27, 680–687. 10.1007/s11655-020-3193-5

  • CrossRef
  • Google Scholar

• 148

  Martemucci G. Costagliola C. Mariano M. D’andrea L. Napolitano P. D’Alessandro A. G. (2022). Free radical properties, source and targets, antioxidant consumption and health. Oxygen2, 48–78. 10.3390/oxygen2020006

  • CrossRef
  • Google Scholar

• 149

  Martínez-Limón A. Joaquin M. Caballero M. Posas F. de Nadal E. (2020). The p38 pathway: from biology to cancer therapy. Int. J. Mol. Sci.21, 1913. 10.3390/ijms21061913

  • CrossRef
  • Google Scholar

• 150

  Maxwell T. Lee K. S. Kim S. Nam K.-S. (2018). Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells. Int. J. Oncol.52, 1339–1349. 10.3892/ijo.2018.4271

  • CrossRef
  • Google Scholar

• 151

  Mendonca P. Soliman K. F. A. (2020). Flavonoids activation of the transcription factor Nrf2 as a hypothesis approach for the prevention and modulation of SARS-CoV-2 infection severity. Antioxidants (Basel)9, 659. 10.3390/antiox9080659

  • CrossRef
  • Google Scholar

• 152

  Meng X. Shao Z. (2021). Ambrosin exerts strong anticancer effects on human breast cancer cells via activation of caspase and inhibition of the Wnt/β-catenin pathway. Trop. J. Pharm. Res.20, 809–814. 10.4314/tjpr.v20i4.22

  • CrossRef
  • Google Scholar

• 153

  Mi X.-J. Choi H. S. Perumalsamy H. Shanmugam R. Thangavelu L. Balusamy S. R. et al (2022). Biosynthesis and cytotoxic effect of silymarin-functionalized selenium nanoparticles induced autophagy mediated cellular apoptosis via downregulation of PI3K/Akt/mTOR pathway in gastric cancer. Phytomedicine99, 154014. 10.1016/j.phymed.2022.154014

  • CrossRef
  • Google Scholar

• 154

  Miatmoko A. Mianing E. A. Sari R. Hendradi E. (2021). Nanoparticles use for delivering ursolic acid in cancer therapy: a scoping review. Front. Pharmacol.12, 787226. 10.3389/fphar.2021.787226

  • CrossRef
  • Google Scholar

• 155

  Mijit M. Caracciolo V. Melillo A. Amicarelli F. Giordano A. (2020). Role of p53 in the regulation of cellular senescence. Biomolecules10, 420. 10.3390/biom10030420

  • CrossRef
  • Google Scholar

• 156

  Miller M. A. Zachary J. F. (2017). “Mechanisms and morphology of cellular injury, adaptation, and death,” in Pathologic basis of veterinary disease. Editor ZacharyJ. F. (Elsevier), 2–43 e19. 10.1016/B978-0-323-35775-3.00001-1

  • CrossRef
  • Google Scholar

• 157

  Min H.-Y. Lee H.-Y. (2023). Cellular dormancy in cancer: mechanisms and potential targeting strategies. Cancer Res. Treat.55, 720–736. 10.4143/crt.2023.468

  • CrossRef
  • Google Scholar

• 158

  Mukhtar E. Adhami V. M. Sechi M. Mukhtar H. (2015). Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett.367, 173–183. 10.1016/j.canlet.2015.07.030

  • CrossRef
  • Google Scholar

• 159

  Musial C. Kuban-Jankowska A. Gorska-Ponikowska M. (2020). Beneficial properties of green tea catechins. Int. J. Mol. Sci.21, 1744. 10.3390/ijms21051744

  • CrossRef
  • Google Scholar

• 160

  Ni J. Wen X. Yao J. Chang H.-C. Yin Y. Zhang M. et al (2005). Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway. Cancer Res.65, 9807–9816. 10.1158/0008-5472.CAN-05-1334

  • CrossRef
  • Google Scholar

• 161

  Noori-Daloii M. R. Momeny M. Yousefi M. Shirazi F. G. Yaseri M. Motamed N. et al (2011). Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med. Oncol. N. Lond. Engl.28, 1395–1404. 10.1007/s12032-010-9603-3

  • CrossRef
  • Google Scholar

• 162

  Nozhat Z. Heydarzadeh S. Memariani Z. Ahmadi A. (2021). Chemoprotective and chemosensitizing effects of apigenin on cancer therapy. Cancer Cell Int.21, 574. 10.1186/s12935-021-02282-3

  • CrossRef
  • Google Scholar

• 163

  Olofinsan K. Abrahamse H. George B. P. (2023). Therapeutic role of alkaloids and alkaloid derivatives in cancer management. Molecules28, 5578. 10.3390/molecules28145578

  • CrossRef
  • Google Scholar

• 164

  Pai J.-T. Hsu M.-W. Leu Y.-L. Chang K.-T. Weng M.-S. (2021). Induction of G2/M cell cycle arrest via p38/p21(Waf1/Cip1)-Dependent signaling pathway activation by bavachinin in non-small-cell lung cancer cells. Molecules26, 5161. 10.3390/molecules26175161

  • CrossRef
  • Google Scholar

• 165

  Pandey N. Tyagi G. Kaur P. Pradhan S. Rajam M. V. Srivastava T. (2020). Allicin overcomes hypoxia mediated cisplatin resistance in lung cancer cells through ROS mediated cell death pathway and by suppressing hypoxia inducible factors. Cell. physiology Biochem.54, 748–766. 10.33594/000000253

  • CrossRef
  • Google Scholar

• 166

  Pang X. He X. Qiu Z. Zhang H. Xie R. Liu Z. et al (2023). Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct. Target. Ther.8, 1. 10.1038/s41392-022-01259-6

  • CrossRef
  • Google Scholar

• 167

  Park C. Jeong J.-W. Han M. H. Lee H. Kim G.-Y. Jin S. et al (2021). The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis. Animal cells Syst.25, 119–127. 10.1080/19768354.2021.1915380

  • CrossRef
  • Google Scholar

• 168

  Park M.-R. Kim S.-G. Cho I.-A. Oh D. Kang K.-R. Lee S.-Y. et al (2015). Licochalcone-A induces intrinsic and extrinsic apoptosis via ERK1/2 and p38 phosphorylation-mediated TRAIL expression in head and neck squamous carcinoma FaDu cells. Food Chem. Toxicol.77, 34–43. 10.1016/j.fct.2014.12.013

  • CrossRef
  • Google Scholar

• 169

  Patel K. Patel D. (2021). Biological activity of ascaridole for the treatment of cancers: phytopharmaceutical importance with molecular study. Ann. Hepato-Biliary-Pancreatic Surg.25, S294. 10.14701/ahbps.EP-93

  • CrossRef
  • Google Scholar

• 170

  Peng R. Xu M. Xie B. Min Q. Hui S. Du Z. et al (2023). Insights on antitumor activity and mechanism of natural benzophenanthridine alkaloids. Molecules28, 6588. 10.3390/molecules28186588

  • CrossRef
  • Google Scholar

• 171

  Pirpour Tazehkand A. Salehi R. Velaei K. Samadi N. (2020). The potential impact of trigonelline loaded micelles on Nrf2 suppression to overcome oxaliplatin resistance in colon cancer cells. Mol. Biol. Rep.47, 5817–5829. 10.1007/s11033-020-05650-w

  • CrossRef
  • Google Scholar

• 172

  Pizzi A. (2021). Tannins medical/pharmacological and related applications: a critical review. Sustain. Chem. Pharm.22, 100481. 10.1016/j.scp.2021.100481

  • CrossRef
  • Google Scholar

• 173

  Qi X. Jha S. K. Jha N. K. Dewanjee S. Dey A. Deka R. et al (2022). Antioxidants in brain tumors: current therapeutic significance and future prospects. Mol. cancer21, 204. 10.1186/s12943-022-01668-9

  • CrossRef
  • Google Scholar

• 174

  Qin R. You F.-M. Zhao Q. Xie X. Peng C. Zhan G. et al (2022). Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets. J. Hematol. Oncol.15, 133. 10.1186/s13045-022-01350-z

  • CrossRef
  • Google Scholar

• 175

  Quideau S. Jourdes M. Lefeuvre D. Montaudon D. Saucier C. Glories Y. et al (2005). The chemistry of wine polyphenolic C-glycosidic ellagitannins targeting human topoisomerase II. Chem.11, 6503–6513. 10.1002/chem.200500428

  • CrossRef
  • Google Scholar

• 176

  Rahmani A. H. Almatroudi A. Allemailem K. S. Alwanian W. M. Alharbi B. F. Alrumaihi F. et al (2023). Myricetin: a significant emphasis on its anticancer potential via the modulation of inflammation and signal transduction pathways. Int. J. Mol. Sci.24, 9665. 10.3390/ijms24119665

  • CrossRef
  • Google Scholar

• 177

  Rahmani A. H. Alsahli M. A. Almatroudi A. Almogbel M. A. Khan A. A. Anwar S. et al (2022). The potential role of apigenin in cancer prevention and treatment. Molecules27, 6051. 10.3390/molecules27186051

  • CrossRef
  • Google Scholar

• 178

  Ratan Z. A. Haidere M. F. Nurunnabi M. Shahriar S. M. Ahammad A. J. S. Shim Y. Y. et al (2020). Green chemistry synthesis of silver nanoparticles and their potential anticancer effects. Cancers12, 855. 10.3390/cancers12040855

  • CrossRef
  • Google Scholar

• 179

  Ray R. Saha S. Paul S. (2022). Two novel compounds, ergosterol and ergosta-5,8-dien-3-ol, from Termitomyces heimii Natarajan demonstrate promising anti-hepatocarcinoma activity. J. Traditional Chin. Med. Sci.9, 443–453. 10.1016/j.jtcms.2022.09.006

  • CrossRef
  • Google Scholar

• 180

  Reddy D. Kumavath R. Barh D. Azevedo V. Ghosh P. (2020). Anticancer and antiviral properties of cardiac glycosides: a review to explore the mechanism of actions. Molecules25, 3596. 10.3390/molecules25163596

  • CrossRef
  • Google Scholar

• 181

  Rigby C. M. Roy S. Deep G. Guillermo-Lagae R. Jain A. K. Dhar D. et al (2017). Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis. Carcinogenesis38, 40–50. 10.1093/carcin/bgw106

  • CrossRef
  • Google Scholar

• 182

  Safi A. Heidarian E. Ahmadi R. (2021). Quercetin synergistically enhances the anticancer efficacy of docetaxel through induction of apoptosis and modulation of PI3K/AKT, MAPK/ERK, and JAK/STAT3 signaling pathways in MDA-MB-231 breast cancer cell line. Int. J. Mol. Cell. Med.10, 11–22. 10.22088/IJMCM.BUMS.10.1.11

  • CrossRef
  • Google Scholar

• 183

  Sali V. K. Mani S. Meenaloshani G. Velmurugan Ilavarasi A. Vasanthi H. R. (2020). Type 5 17-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3) inhibition and potential anti-proliferative activity of cholest-4-ene-3,6-dione in MCF-7 breast cancer cells. Steroids159, 108638. 10.1016/j.steroids.2020.108638

  • CrossRef
  • Google Scholar

• 184

  Sanchez-Martin V. Plaza-Calonge M. D. C. Soriano-Lerma A. Ortiz-Gonzalez M. Linde-Rodriguez A. Perez-Carrasco V. et al (2022). Gallic acid: a natural phenolic compound exerting antitumoral activities in colorectal cancer via interaction with G-quadruplexes. Cancers14, 2648. 10.3390/cancers14112648

  • CrossRef
  • Google Scholar

• 185

  Santarpia L. Lippman S. M. El-Naggar A. K. (2012). Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin. Ther. targets16, 103–119. 10.1517/14728222.2011.645805

  • CrossRef
  • Google Scholar

• 186

  Schiliro C. Firestein B. L. (2021). Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation. Cells10, 1056. 10.3390/cells10051056

  • CrossRef
  • Google Scholar

• 187

  Schneider-Brachert W. Heigl U. Ehrenschwender M. (2013). Membrane trafficking of death receptors: implications on signalling. Int. J. Mol. Sci.14, 14475–14503. 10.3390/ijms140714475

  • CrossRef
  • Google Scholar

• 188

  Senthamizh N. Vidhyavathi R. Raj E. Lobo V. Ramu A. (2020). Reserpine subdued non-small cell lung cancer cells via ROS-mediated apoptosis. J. Conventional Knowl. Holist. Health4, 1–4. 10.53517/JCKHH.2581-3331.422020206

  • CrossRef
  • Google Scholar

• 189

  Shen J. Yang Z. Wu X. Yao G. Hou M. (2023). Baicalein facilitates gastric cancer cell apoptosis by triggering endoplasmic reticulum stress via repression of the PI3K/AKT pathway. Appl. Biol. Chem.66, 10. 10.1186/s13765-022-00759-x

  • CrossRef
  • Google Scholar

• 190

  Shi R.-X. Ong C.-N. Shen H.-M. (2004). Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene23, 7712–7721. 10.1038/sj.onc.1208046

  • CrossRef
  • Google Scholar

• 191

  Shiau J.-P. Chuang Y.-T. Tang J.-Y. Yang K.-H. Chang F.-R. Hou M.-F. et al (2022). The impact of oxidative stress and AKT pathway on cancer cell functions and its application to natural products. Antioxidants11, 1845. 10.3390/antiox11091845

  • CrossRef
  • Google Scholar

• 192

  Si L. Fu J. Liu W. Hayashi T. Nie Y. Mizuno K. et al (2020). Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Mol. Cell. Biochem.463, 189–201. 10.1007/s11010-019-03640-6

  • CrossRef
  • Google Scholar

• 193

  Siegmund D. Kums J. Ehrenschwender M. Wajant H. (2016). Activation of TNFR2 sensitizes macrophages for TNFR1-mediated necroptosis. Cell death Dis.7, e2375. 10.1038/cddis.2016.285

  • CrossRef
  • Google Scholar

• 194

  Silva L. C. Borgato G. B. Wagner V. P. Martins M. D. Rocha G. Z. Lopes M. A. et al (2022). Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells. J. oral pathology Med.51, 553–562. 10.1111/jop.13252

  • CrossRef
  • Google Scholar

• 195

  Simanullang R. H. Situmorang P. C. Herlina M. Noradina S. B. Manurung S. S. (2022a). Histological changes of cervical tumours following Zanthoxylum acanthopodium DC treatment, and its impact on cytokine expression. Saudi J. Biol. Sci.29 (4), 2706–2718. 10.1016/j.sjbs.2021.12.065

  • CrossRef
  • Google Scholar

• 196

  Simanullang R. H. Situmorang P. C. Herlina M. N. Silalahi B. (2022c). Cytochrome c expression by andaliman (Zanthoxylum acanthopodium) on cervical cancer histology. Pak J. Biol. Sci.25 (1), 49–55. 10.3923/pjbs.2022.49.55

  • CrossRef
  • Google Scholar

• 197

  Simanullang R. H. Situmorang P. C. Siahaan J. M. Widjaja S. S. Mutiara M. (2022b). Effects of Zanthoxylum acanthopodium on MMP-9 and GLUT-1 expression and histology changes in rats with cervical carcinoma. Pharmacia69 (4), 911–920. 10.3897/pharmacia.69.e89368

  • CrossRef
  • Google Scholar

• 198

  Singh A. K. Vinayak M. (2017). Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation. Inflamm. Res.66, 911–921. 10.1007/s00011-017-1072-0

  • CrossRef
  • Google Scholar

• 199

  Situmorang P. C. Ilyas S. (2018). Review: germinal cell apoptosis by herbal medicine. Asian J Pharm. Clin. Res.11 (9), 24–31. 10.22159/ajpcr.2018.v11i9.26400

  • CrossRef
  • Google Scholar

• 200

  Situmorang P. C. Ilyas S. Hutahaean S. Rosidah R. (2021a). Components and acute toxicity of nano herbal haramonting (Rhodomyrtus tomentosa). J. Herbmed Pharmacol.10, 139–148. 10.34172/jhp.2021.15

  • CrossRef
  • Google Scholar

• 201

  Situmorang P. C. Ilyas S. Hutahaean S. Rosidah R. (2021b). Effect of nano herbal andaliman (Zanthoxylum acanthopodium) fruits in NOTCH1 and Hes1 expressions to human placental trophoblasts. Pak J. Biol. Sci.24 (1), 165–171. 10.3923/pjbs.2021.165.171

  • CrossRef
  • Google Scholar

• 202

  Situmorang P. C. Ilyas S. Hutahaean S. Rosidah R. (2021c). Histological changes in placental rat apoptosis via FasL and cytochrome c by the nano-herbal Zanthoxylum acanthopodium. Saudi J. Bio Sci.28 (5), 3060–3068. 10.1016/j.sjbs.2021.02.047

  • CrossRef
  • Google Scholar

• 203

  Situmorang P. C. Ilyas S. Siahaan D. A. S. Restuati M. Sari E. R. Chairunisa C. et al (2022b). Effect of Rhodomyrtus tomentosa Hassk. on HIF1α and VEGF expressions on hypertension placental. J. Pharm. Pharmacogn. Res.10 (6), 1076–1086. 10.56499/jppres22.1517_10.6.1076

  • CrossRef
  • Google Scholar

• 204

  Situmorang P. C. Ilyas S. Syahputra R. A. Nugraha A. P. Putri M. S. S. Rumahorbo C. G. P. (2024a). Rhodomyrtus tomentosa (Aiton) Hassk. (haramonting) protects against allethrin-exposed pulmo damage in rats:mechanistic interleukins. Front. Pharmacol.15, 1343936. 10.3389/fphar.2024.1343936

  • CrossRef
  • Google Scholar

• 205

  Situmorang P. C. Ilyas S. Syahputra R. A. Sari R. M. Nugraha A. P. Ibrahim A. (2024b). Rhodomyrtus tomentosa as a new anticancer molecular strategy in breast histology via Her2, IL33, EGFR, and MUC1. Front. Pharmacol.15, 1345645. 10.3389/fphar.2024.1345645

  • CrossRef
  • Google Scholar

• 206

  Situmorang P. C. Simanullang R. H. Syahputra R. A. Hutahaean M. M. Sembiring H. Nisfa L. et al (2023). Histological analysis of TGFβ1 and VEGFR expression in cervical carcinoma treated with Rhodomyrtus tomentosa. Pharmacia70 (1), 217–223. 10.3897/pharmacia.70.e96811

  • CrossRef
  • Google Scholar

• 207

  Situmorang P. C. Syahputra R A. Simanullang R. H. (2022a). EGFL7 and HIF-1a expression on human trophoblast placental by Rhodomyrtus tomentosa and Zanthoxylum acanthopodium. Pak J. Biol. Sci.25 (2), 123–130. 10.3923/pjbs.2022.123.130

  • CrossRef
  • Google Scholar

• 208

  Škubník J. Pavlíčková V. S. Ruml T. Rimpelová S. (2021). Vincristine in combination therapy of cancer: emerging trends in clinics. Biology10, 849. 10.3390/biology10090849

  • CrossRef
  • Google Scholar

• 209

  Sohel M. Sultana H. Sultana T. Al Amin M. Aktar S. Ali M. C. et al (2022). Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: a comprehensive review. Heliyon8, e08815. 10.1016/j.heliyon.2022.e08815

  • CrossRef
  • Google Scholar

• 210

  Son H.-K. Kim D. (2023). Quercetin induces cell cycle arrest and apoptosis in YD10B and YD38 oral squamous cell carcinoma cells. Asian Pac. J. cancer Prev. APJCP24, 283–289. 10.31557/APJCP.2023.24.1.283

  • CrossRef
  • Google Scholar

• 211

  Srinivasan S. Koduru S. Kumar R. Venguswamy G. Kyprianou N. Damodaran C. (2009). Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells. Int. J. cancer125, 961–967. 10.1002/ijc.24419

  • CrossRef
  • Google Scholar

• 212

  Subramaniam A. Loo S. Y. Rajendran P. Manu K. A. Perumal E. Li F. et al (2013). An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins. Apoptosis Int. J. Program. Cell death18, 1175–1187. 10.1007/s10495-013-0851-5

  • CrossRef
  • Google Scholar

• 213

  Sun L. Yuan W. Wen G. Yu B. Xu F. Gan X. et al (2020). Parthenolide inhibits human lung cancer cell growth by modulating the IGF-1R/PI3K/Akt signaling pathway. Oncol. Rep.44, 1184–1193. 10.3892/or.2020.7649

  • CrossRef
  • Google Scholar

• 214

  Sun M.-Y. Bhaskar S. M. M. (2022). When two maladies meet: disease burden and pathophysiology of stroke in cancer. Int. J. Mol. Sci.23, 15769. 10.3390/ijms232415769

  • CrossRef
  • Google Scholar

• 215

  Suo F. Zhou X. Setroikromo R. Quax W. J. (2022). Receptor specificity engineering of TNF superfamily ligands. Pharmaceutics14, 181. 10.3390/pharmaceutics14010181

  • CrossRef
  • Google Scholar

• 216

  Takáč P. Michalková R. Čižmáriková M. Bedlovičová Z. Balážová Ľ. Takáčová G. (2023). The role of silver nanoparticles in the diagnosis and treatment of cancer: are there any perspectives for the future?Life (Basel)13, 466. 10.3390/life13020466

  • CrossRef
  • Google Scholar

• 217

  Talib W. H. Alsalahat I. Daoud S. Abutayeh R. F. Mahmod A. I. (2020). Plant-derived natural products in cancer research: extraction, mechanism of action, and drug formulation. Molecules25, 5319. 10.3390/molecules25225319

  • CrossRef
  • Google Scholar

• 218

  Tayarani-Najaran Z. Tayarani-Najaran N. Eghbali S. (2021). A review of auraptene as an anticancer agent. Front. Pharmacol.12, 698352. 10.3389/fphar.2021.698352

  • CrossRef
  • Google Scholar

• 219

  Tayeh M. Watanapokasin R. (2020). Antimetastatic potential of rhodomyrtone on human chondrosarcoma SW1353 cells. Evidence-based complementary Altern. Med. eCAM2020, 8180261. 10.1155/2020/8180261

  • CrossRef
  • Google Scholar

• 220

  Tian Z. Sun C. Liu J. (2022). Pelargonidin inhibits vascularization and metastasis of brain gliomas by blocking the PI3K/AKT/mTOR pathway. J. Biosci.47, 64. 10.1007/s12038-022-00281-8

  • CrossRef
  • Google Scholar

• 221

  Tran S. Fairlie W. D. Lee E. F. (2021). BECLIN1: protein structure, function and regulation. Cells10, 1522. 10.3390/cells10061522

  • CrossRef
  • Google Scholar

• 222

  Tsai C.-H. Yang C.-W. Wang J.-Y. Tsai Y.-F. Tseng L.-M. King K.-L. et al (2013). Timosaponin AIII suppresses hepatocyte growth factor-induced invasive activity through sustained ERK activation in breast cancer MDA-MB-231 cells. Evidence-based complementary Altern. Med. eCAM2013, 421051. 10.1155/2013/421051

  • CrossRef
  • Google Scholar

• 223

  Tyagi A. Sharma S. Wu K. Wu S.-Y. Xing F. Liu Y. et al (2021). Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat. Commun.12, 474. 10.1038/s41467-020-20733-9

  • CrossRef
  • Google Scholar

• 224

  Verma A. K. Bharti P. S. Rafat S. Bhatt D. Goyal Y. Pandey K. K. et al (2021). Autophagy paradox of cancer: role, regulation, and duality. Oxidative Med. Cell. Longev.2021, 8832541. 10.1155/2021/8832541

  • CrossRef
  • Google Scholar

• 225

  Villareal M. O. Chaochaiphat T. Bejaoui M. Sato K. Isoda H. City T. et al (2020). Tara tannin regulates pigmentation by modulating melanogenesis enzymes and melanosome transport proteins expression. Planta Medica Int. Open7 (01), e34–e44. 10.1055/a-1141-0151

  • CrossRef
  • Google Scholar

• 226

  Vodanovich D. A. M Choong P. F. (2018). Soft-tissue sarcomas. Indian J. Orthop.52, 35–44. 10.4103/ortho.IJOrtho_220_17

  • CrossRef
  • Google Scholar

• 227

  Wahi A. Bishnoi M. Raina N. Singh M. A. Verma P. Gupta P. K. et al (2023). Recent updates on nano-phyto-formulations based therapeutic intervention for cancer treatment. Oncol. Res.32, 19–47. 10.32604/or.2023.042228

  • CrossRef
  • Google Scholar

• 228

  Wang B.-F. Wang X.-J. Kang H.-F. Bai M.-H. Guan H.-T. Wang Z.-W. et al (2014a). Saikosaponin-D enhances radiosensitivity of hepatoma cells under hypoxic conditions by inhibiting hypoxia-inducible factor-1α. Cell. physiology Biochem.33, 37–51. 10.1159/000356648

  • CrossRef
  • Google Scholar

• 229

  Wang F. Chang Z. Fan Q. Wang L. (2014b). Epigallocatechin-3-gallate inhibits the proliferation and migration of human ovarian carcinoma cells by modulating p38 kinase and matrix metalloproteinase-2. Mol. Med. Rep.9, 1085–1089. 10.3892/mmr.2014.1909

  • CrossRef
  • Google Scholar

• 230

  Wang J. Li J. Cao N. Li Z. Han J. Li L. (2018). Resveratrol, an activator of SIRT1, induces protective autophagy in non-small-cell lung cancer via inhibiting Akt/mTOR and activating p38-MAPK. OncoTargets Ther.11, 7777–7786. 10.2147/OTT.S159095

  • CrossRef
  • Google Scholar

• 231

  Wang M. Yu F. Zhang Y. Chang W. Zhou M. (2022). The effects and mechanisms of flavonoids on cancer prevention and therapy: focus on gut microbiota. Int. J. Biol. Sci.18, 1451–1475. 10.7150/ijbs.68170

  • CrossRef
  • Google Scholar

• 232

  Wei L. Jin X. Cao Z. Li W. (2016). Evodiamine induces extrinsic and intrinsic apoptosis of ovarian cancer cells via the mitogen-activated protein kinase/phosphatidylinositol-3-kinase/protein kinase B signaling pathways. J. traditional Chin. Med.36, 353–359. 10.1016/s0254-6272(16)30049-8

  • CrossRef
  • Google Scholar

• 233

  Wei M. Li J. Qiu J. Yan Y. Wang H. Wu Z. et al (2020). Costunolide induces apoptosis and inhibits migration and invasion in H1299 lung cancer cells. Oncol. Rep.43, 1986–1994. 10.3892/or.2020.7566

  • CrossRef
  • Google Scholar

• 234

  Weledji E. P. Orock G. E. (2015). Surgery for non-hodgkin’s lymphoma. Oncol. Rev.9, 274. 10.4081/oncol.2015.274

  • CrossRef
  • Google Scholar

• 235

  Wolfrum P. Fietz A. Schnichels S. Hurst J. (2022). The function of p53 and its role in Alzheimer’s and Parkinson’s disease compared to age-related macular degeneration. Front. Neurosci.16, 1029473. 10.3389/fnins.2022.1029473

  • CrossRef
  • Google Scholar

• 236

  Woo S.-M. Choi Y. K. Kim A. J. Cho S.-G. Ko S.-G. (2016). p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells. Mol. Med. Rep.13, 1091–1096. 10.3892/mmr.2015.4672

  • CrossRef
  • Google Scholar

• 237

  Wróblewska-Łuczka P. Cabaj J. Bargieł J. Łuszczki J. J. (2023). Anticancer effect of terpenes: focus on malignant melanoma. Pharmacol. Rep. P. R.75, 1115–1125. 10.1007/s43440-023-00512-1

  • CrossRef
  • Google Scholar

• 238

  Wu D. Liu Z. Li J. Zhang Q. Zhong P. Teng T. et al (2019). Epigallocatechin-3-gallate inhibits the growth and increases the apoptosis of human thyroid carcinoma cells through suppression of EGFR/RAS/RAF/MEK/ERK signaling pathway. Cancer Cell Int.19, 43. 10.1186/s12935-019-0762-9

  • CrossRef
  • Google Scholar

• 239

  Wu H. Du J. Li C. Li H. Guo H. Li Z. (2022a). Kaempferol can reverse the 5-fu resistance of colorectal cancer cells by inhibiting PKM2-mediated glycolysis. Int. J. Mol. Sci.23, 3544. 10.3390/ijms23073544

  • CrossRef
  • Google Scholar

• 240

  Wu M.-F. Huang Y.-H. Chiu L.-Y. Cherng S.-H. Sheu G.-T. Yang T.-Y. (2022b). Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-regulated p38 MAPK phosphorylation. Int. J. Mol. Sci.23, 8248. 10.3390/ijms23158248

  • CrossRef
  • Google Scholar

• 241

  Xi H. Wang S. Wang B. Hong X. Liu X. Li M. et al (2022). The role of interaction between autophagy and apoptosis in tumorigenesis (Review). Oncol. Rep.48, 208. 10.3892/or.2022.8423

  • CrossRef
  • Google Scholar

• 242

  Xiao J. Gao M. Fei B. Huang G. Diao Q. (2020). Nature-derived anticancer steroids outside cardica glycosides. Fitoterapia147, 104757. 10.1016/j.fitote.2020.104757

  • CrossRef
  • Google Scholar

• 243

  Xie X. Zhang L. Zhang W. Tayebee R. Hoseininasr A. Vatanpour H. et al (2020). Fabrication of temperature and pH sensitive decorated magnetic nanoparticles as effective biosensors for targeted delivery of acyclovir anti-cancer drug. J. Mol. Liq.309, 113024. 10.1016/j.molliq.2020.113024

  • CrossRef
  • Google Scholar

• 244

  Yamada M. Iijima Y. Seo M. Hino S. Sano M. Sakagami H. et al (2023). Cancer chemotherapy-associated pigmentation of the oral mucosa. vivo (Athens, Greece)37, 1880–1885. 10.21873/invivo.13280

  • CrossRef
  • Google Scholar

• 245

  Yang J. Yang Y. Tian L. Sheng X.-F. Liu F. Cao J.-G. (2011). Casticin-induced apoptosis involves death receptor 5 upregulation in hepatocellular carcinoma cells. World J. gastroenterology17, 4298–4307. 10.3748/wjg.v17.i38.4298

  • CrossRef
  • Google Scholar

• 246

  Yang L. Zhang W. Chopra S. Kaur D. Wang H. Li M. et al (2020). The epigenetic modification of epigallocatechin gallate (EGCG) on cancer. Curr. drug targets21, 1099–1104. 10.2174/1389450121666200504080112

  • CrossRef
  • Google Scholar

• 247

  Yao H. Chen Y. Zhang L. He X. He X. Lian L. et al (2014). Carnosol inhibits cell adhesion molecules and chemokine expression by tumor necrosis factor-α in human umbilical vein endothelial cells through the nuclear factor-κB and mitogen-activated protein kinase pathways. Mol. Med. Rep.9, 476–480. 10.3892/mmr.2013.1839

  • CrossRef
  • Google Scholar

• 248

  You Y. Wang R. Shao N. Zhi F. Yang Y. (2019). Luteolin suppresses tumor proliferation through inducing apoptosis and autophagy via MAPK activation in glioma. OncoTargets Ther.12, 2383–2396. 10.2147/OTT.S191158

  • CrossRef
  • Google Scholar

• 249

  Yuan B. Yang R. Ma Y. Zhou S. Zhang X. Liu Y. (2017). A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications. Pharm. Biol.55, 620–635. 10.1080/13880209.2016.1262433

  • CrossRef
  • Google Scholar

• 250

  Yuan M. Zhang G. Bai W. Han X. Li C. Bian S. (2022). The role of bioactive compounds in natural products extracted from plants in cancer treatment and their mechanisms related to anticancer effects. Oxidative Med. Cell. Longev.2022, 1429869. 10.1155/2022/1429869

  • CrossRef
  • Google Scholar

• 251

  Yusuf A. Almotairy A. R. Z. Henidi H. Alshehri O. Y. Aldughaim M. S. (2023). Nanoparticles as drug delivery systems: a review of the implication of nanoparticles’ physicochemical properties on responses in biological systems. Polymers15, 1596. 10.3390/polym15071596

  • CrossRef
  • Google Scholar

• 252

  Zaafar D. Khalil H. M. A. Rasheed R. A. Eltelbany R. F. A. Zaitone S. A. (2022). Hesperetin mitigates sorafenib-induced cardiotoxicity in mice through inhibition of the TLR4/NLRP3 signaling pathway. PloS one17, e0271631. 10.1371/journal.pone.0271631

  • CrossRef
  • Google Scholar

• 253

  Zeng Q. Che Y. Zhang Y. Chen M. Guo Q. Zhang W. (2020). Thymol isolated from thymus vulgaris L. Inhibits colorectal cancer cell growth and metastasis by suppressing the wnt/β-catenin pathway. Drug Des. Dev. Ther.14, 2535–2547. 10.2147/DDDT.S254218

  • CrossRef
  • Google Scholar

• 254

  Zhang G. Li Z. Dong J. Zhou W. Zhang Z. Que Z. et al (2022). Acacetin inhibits invasion, migration and TGF-β1-induced EMT of gastric cancer cells through the PI3K/Akt/Snail pathway. BMC complementary Med. Ther.22, 10. 10.1186/s12906-021-03494-w

  • CrossRef
  • Google Scholar

• 255

  Zhang L. Yang C. Huang Y. Huang H. Yuan X. Zhang P. et al (2021a). Cardamonin inhibits the growth of human osteosarcoma cells through activating P38 and JNK signaling pathway. Biomed. Pharmacother. = Biomedecine Pharmacother.134, 111155. 10.1016/j.biopha.2020.111155

  • CrossRef
  • Google Scholar

• 256

  Zhang R. Hao J. Wu Q. Guo K. Wang C. Zhang W. K. et al (2020). Dehydrocostus lactone inhibits cell proliferation and induces apoptosis by PI3K/Akt/Bad and ERS signalling pathway in human laryngeal carcinoma. J. Cell. Mol. Med.24, 6028–6042. 10.1111/jcmm.15131

  • CrossRef
  • Google Scholar

• 257

  Zhang Y. Yuan B. Bian B. Zhao H. Kiyomi A. Hayashi H. et al (2021b). Cytotoxic effects of hellebrigenin and arenobufagin against human breast cancer cells. Front. Oncol.11, 711220. 10.3389/fonc.2021.711220

  • CrossRef
  • Google Scholar

• 258

  Zhao X. Liu Z. Ren Z. Wang H. Wang Z. Zhai J. et al (2020). Triptolide inhibits pancreatic cancer cell proliferation and migration via down-regulating PLAU based on network pharmacology of Tripterygium wilfordii Hook F. Eur. J. Pharmacol.880, 173225. 10.1016/j.ejphar.2020.173225

  • CrossRef
  • Google Scholar

• 259

  Zhao X. Tao X. Xu L. Yin L. Qi Y. Xu Y. et al (2016). Dioscin induces apoptosis in human cervical carcinoma HeLa and SiHa cells through ROS-mediated DNA damage and the mitochondrial signaling pathway. Molecules21, 730. 10.3390/molecules21060730

  • CrossRef
  • Google Scholar

• 260

  Zhao Y. Pan H. Liu W. Liu E. Pang Y. Gao H. et al (2023). Menthol: an underestimated anticancer agent. Front. Pharmacol.14, 1148790. 10.3389/fphar.2023.1148790

  • CrossRef
  • Google Scholar

• 261

  Zhao Z. Jiang Y. Liu Z. Li Q. Gao T. Zhang S. (2021). Ampelopsin inhibits cell viability and metastasis in renal cell carcinoma by negatively regulating the PI3K/AKT signaling pathway. Evidence-based complementary Altern. Med.2021, 4650566. 10.1155/2021/4650566

  • CrossRef
  • Google Scholar

• 262

  Zhou B.-G. Wei C.-S. Zhang S. Zhang Z. Gao H.-M. (2018). Matrine reversed multidrug resistance of breast cancer MCF-7/ADR cells through PI3K/AKT signaling pathway. J. Cell. Biochem.119, 3885–3891. 10.1002/jcb.26502

  • CrossRef
  • Google Scholar

• 263

  Zhou Q. Wang S. Zhang H. Lu Y. Wang X. Motoo Y. et al (2009). The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells. Acta Pharmacol. Sin.30, 1648–1658. 10.1038/aps.2009.166

  • CrossRef
  • Google Scholar

• 264

  Zhou W. Cao W. Wang M. Yang K. Zhang X. Liu Y. et al (2023). Validation of quercetin in the treatment of colon cancer with diabetes via network pharmacology, molecular dynamics simulations, and in vitro experiments. Mol. Divers. 10.1007/s11030-023-10725-4

  • CrossRef
  • Google Scholar

• 265

  Zhu M.-L. Zhang P.-M. Jiang M. Yu S.-W. Wang L. (2020). Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells. BMC complementary Med. Ther.20, 209. 10.1186/s12906-020-02965-w

  • CrossRef
  • Google Scholar

• 266

  Zubor P. Dankova Z. Kolkova Z. Holubekova V. Brany D. Mersakova S. et al (2020). Rho GTPases in gynecologic cancers: in-depth analysis toward the paradigm change from reactive to predictive, preventive, and personalized medical approach benefiting the patient and healthcare. Cancers12, 1292. 10.3390/cancers12051292

  • CrossRef
  • Google Scholar