Putri Cahaya Situmorang1*
Syafruddin Ilyas1
Sony Eka Nugraha2
Rony Abdi Syahputra3
Nik Mohd Afizan Nik Abd Rahman4- 1Study Program of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, Indonesia
- 2Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
- 3Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
- 4Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
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. MAPK/ERK pathway in cancer. The activation of MAPK initiates with the stimulation of receptor tyrosine kinase (RTK) in the MAPK/ERK signaling pathway. This leads to the activation of RAF kinase protein kinase activity through Ras activation. Subsequently, MEK (MEK1 and MEK2) is phosphorylated and activated by RAF kinase. Finally, ERK is activated and phosphorylated by MEK (https://www.sinobiological.com/pathways).
Table 1. Mechanism of action of various phytochemical compounds in the MAPK/ERK pathway in cancer.
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. TNF-signaling pathways in cancer. Tumor necrosis factor (TNF) exerts its actions through the tumor necrosis factor receptor (TNFR), hence engaging in the extrinsic pathway to promote apoptosis. The interaction between the TNFR and procaspases is facilitated by adapter proteins, such as FADD and TRADD. These adapter proteins possess the capability to cleave inactive procaspases, hence activating the caspase cascade. This series of events ultimately results in the irreversible initiation of cell death (https://www.sinobiological.com/pathways).
Table 2. Mechanism of action of various phytochemical compounds in TNF signaling in cancer.
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. Death receptor pathways in cancer. Activation of these receptors by specific ligands triggers the recruitment of multiple molecules to the death domain, which then initiates a signaling cascade. There are two distinct forms of death receptor signaling complexes. The first group comprises death-inducing signaling complexes (DISCs) that activate caspase-8, a crucial component in apoptotic signaling transduction. DISCs are formed at the CD95, TRAILR1, or TRAILR2 receptors. These processes involve the recruitment of various molecules that facilitate apoptotic and survival signal transduction (https://www.sinobiological.com/pathways).
Table 3. Mechanism of action of phytochemical compounds in the death receptor pathways in cancer.
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. p53 pathways in cancer. The p53 mechanism occurs due to various stress stimuli, such as DNA damage, nucleolar stress, metabolic stress, and oncogenic stress. p53 protein levels show stability. Proteasome-dependent degradation of p53 is facilitated by E3 ligases, which enhance ubiquitination, and cytoplasmic connections between p53 and Bcl-2 family proteins have also been observed to promote apoptosis (https://www.sinobiological.com/pathways).
Table 4. Mechanism of action of phytochemical compounds in the p53 pathway in cancer.
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. p38 pathways in cancer. p38 MAPK governs the regulation of downstream targets, including different kinases, transcription factors, and cytosolic proteins. The kinases included in this study are MAPKAPK2, MAPKAPK3, PRAK, MSK1, and MNK ½. P38 phosphorylates various important transcription factors, including 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. The p38 MAPK pathway is essential for controlling the synthesis of pro-inflammatory cytokines at both the transcriptional and translational stages (https://www.sinobiological.com/pathways).
Table 5. Mechanism of action of phytochemical compounds in the p38 pathway in cancer.
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. Actin dynamics signaling pathways in cancer. The large protein tyrosine kinase family includes receptor tyrosine kinases (RTKs). Tyrosine kinase receptors, such as EGFR, PDGFR, MCSFR, IGF1R, INSR, NGFR, FGFR, VEGFR, and HGFR, modulate intracellular signals that control the cell’s response to external stimulus and are part of the Ras superfamily of tiny GTP-binding proteins that are involved in many biological processes (https://www.sinobiological.com/pathways).
Table 6. Mechanism of action of phytochemical compounds in actin dynamics signaling in cancer.
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. Autophagy pathways in cancer. Activating mTOR (Akt and MAPK signaling) in cancer suppresses autophagy, while negative regulation (AMK and p53 signaling) enhances it. Both autophagy and apoptosis have beneficial and negative effects, and they communicate. Under nutritional constraint, autophagy aids survival. Other pro-apoptotic signals including TNF, TRAIL, and FADD trigger autophagy (https://www.sinobiological.com/pathways).
Table 7. Mechanism of action of phytochemical compounds in autophagy pathways in cancer.
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. Phytochemicals as chemo-preventives and signaling molecule modulators. In the presence of phytochemicals that increase p53, decrease AKT, and cause cellular apoptosis and cell cycle arrest, tumor suppressor proteins activate the apoptotic cascade. Crosstalk between the p53, MAPK, and JNK pathways also contributes, where the AKT and mTOR pathways are downregulated in cancer cells, causing autophagy, but the presence of herbal phytochemicals can control inflammation, angiogenesis, invasion, and metastasis (Ahmed et al., 2022).
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.
Author contributions
PS: funding acquisition, methodology, writing–original draft, and writing–review and editing. SI: software, supervision, writing–original draft, and writing–review and editing. SN: formal analysis, investigation, project administration, writing–original draft, and writing–review and editing. RS: formal analysis, writing–original draft, and writing–review and editing. NN: conceptualization, resources, visualization, writing–original draft, and writing–review and editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was support by the LPDP in Equity project research PKUU-PT QS WUR RANK 102-300 scheme under contract numbers 7092.1/UN5.1.R/PPM/2023 and 8/UN5.2.3.1/PPM/KPEP/2023.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1387866/full#supplementary-material
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Keywords: apoptosis, cancer, herbal, molecular pathway, phytochemicals, plants
Citation: Situmorang PC, Ilyas S, Nugraha SE, Syahputra RA and Nik Abd Rahman NMA (2024) Prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways. Front. Pharmacol. 15:1387866. doi: 10.3389/fphar.2024.1387866
Received: 18 February 2024; Accepted: 17 June 2024;
Published: 22 July 2024.
Edited by:
Chunbo He, University of Oklahoma Health Sciences Center, United StatesReviewed by:
Seyed Zachariah Moradi, Kermanshah University of Medical Sciences, IranVenkataswarup Tiriveedhi, Tennessee State University, United States
Copyright © 2024 Situmorang, Ilyas, Nugraha, Syahputra and Nik Abd Rahman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Putri Cahaya Situmorang, cHV0cmkuY2FoYXlhQHVzdS5hYy5pZA==