Reversal of chemotherapy resistance in gastric cancer with traditional Chinese medicine as sensitizer: potential mechanism of action

Abstract

Gastric cancer (GC) remains one of the most common types of cancer, ranking fifth among cancer-related deaths worldwide. Chemotherapy is an effective treatment for advanced GC. However, the development of chemotherapy resistance, which involves the malfunction of several signaling pathways and is the consequence of numerous variables interacting, seriously affects patient treatment and leads to poor clinical outcomes. Therefore, in order to treat GC, it is imperative to find novel medications that will increase chemotherapy sensitivity and reverse chemotherapy resistance. Traditional Chinese medicine (TCM) has been extensively researched as an adjuvant medication in recent years. It has been shown to have anticancer benefits and to be crucial in enhancing chemotherapy sensitivity and reducing chemotherapy resistance. Given this, the mechanism of treatment resistance in GC is summed up in this work. The theoretical foundation for TCM as a sensitizer in adjuvant treatment of GC is established by introducing the primary signal pathways and possible targets implicated in improving chemotherapy sensitivity and reversing chemotherapy resistance of GC by TCM and active ingredients.

1 Introduction

According to global cancer statistics 2022, gastric cancer (GC) ranks fifth in terms of incidence and mortality, seriously threatening human health (1). Endoscopic resection is the main treatment for early-stage GC. Non-early operable GC is treated with surgery (2). Unfortunately, most patients are diagnosed with advanced unresectable or metastatic stages of disease at first, due to the lack of specific clinical symptoms.

In comparison to supportive therapy alone, combined chemotherapy can improve both survival rates and quality of life for patients with advanced or metastatic disease. A platinum fluoropyrimidine doublet has been the first-line therapy due to lower toxicity (3). Oxaliplatin is recommended for older patients because of its lower toxicity than cisplatin (4). First-line treatment based on irinotecan may be recommended as a first-line therapy option in patients with advanced or metastatic gastroesophageal cancer (3, 5, 6). For patients with Human Epidermal Growth Factor Receptor 2 (HER2) overexpression positive GC, Trastuzumab should be added to first-line chemotherapy [category 1 for cisplatin (7); category 2A for oxaliplatin] (3). Pembrolizumab can be added to this regimen to improve progression-free survival (8). When patients with HER2 overexpression are negative, the preferred regimen for Programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)≥5 is nivolumab combined with fluorouracil and oxaliplatin (9). The selection of second-line and subsequent therapy is determined by performance status and the history of prior treatments. As a monotherapy or in combination with paclitaxel, ramucirumab is the preferred option for second-line and subsequent therapy (10, 11). As monotherapy or combination, docetaxel, paclitaxel, and irinotecan are recommended as a second-line therapy (12–14). The regimen of trifluridine and tipiracil is classified as category 1 recommendations for patients whose disease progressed after second-line chemotherapy (15). This treatment is suitable only for patients with low-volume GC, because of its strong cytotoxicity.

However, parts of GC cells escape cell toxicity and acquire stably resistant to drug during chemotherapy. The acquired resistance leads poor clinical efficacy and is the leading cause of chemotherapy failure in most patients. Currently, there are several strategies for overcoming chemoresistance in cancer, including discontinuous dosing, modifying drug concentrations, combination therapy, and the use of natural products (16). However, most of these strategies generally result in serious side effects, involve higher treatment costs, and technical difficulties (17). Natural products play an important role in treatment of diseases, especially for cancer and infection diseases. It has been reported that about half of the anti-cancer drugs approved by the Food Drug Administration (FDA) originate from either natural products or their derivatives (18). Traditional Chinese Medicine (TCM) has been extensively used clinically due to its strong specificity, high efficacy, and low toxicity. It not only inhibits tumor growth but also enhances chemotherapy efficacy and reverses chemoresistance when combined with traditional chemotherapy.

In this review, we aim to understand the mechanisms of chemotherapy resistance in GC and to explore the potential of TCM and its active components as chemotherapy sensitizers in reversing chemotherapy resistance and improving curative effect in GC. We hope TCM can be an innovative strategy to solve the difficulties of clinical anti-cancer treatments.

2 Mechanisms of chemoresistance for GC manuscript formatting

2.1 Drug efflux

The intracellular concentration of antitumor drugs needs to remain within the effective concentration range to exert therapeutic effects. Compared with that in normal tumor cells, the intracellular drug concentration in resistant cells is well below the effective range due to enhanced drug efflux, reduced drug influx and drug sequestration (19). Chromodomain helicase DNA-binding protein 4 (CHD4) increases the cisplatin efflux and decrease the intracellular concentration, leading to drug resistance (20). Therefore, abnormally high expression of associated membrane proteins which mediate drug efflux is one of the causes leading to chemotherapy resistance (Figure 1). ATP-mediated ATP-binding cassette (ABC) transporter family is a major class of these membrane proteins. The level of the classical drug resistance-related protein P-glycoprotein (P-gp) gradually increases in gastric epithelial cells, GC cells and drug-resistant cells (21). PD-L1 promotes the expression of P-gp, by up-regulating the phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt) signal pathway to enhance drug efflux and reduce the cell damage caused by cisplatin (22). One study found that a selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor could enhance oxaliplatin-induced apoptosis by down-regulating the expression of p-gp (23). In addition, the function of ABC transporters, including P-gp, also relies on their subcellular location. A study showed that ABC transporters were more localized to the plasma membrane in SGC-7901 cells than in resistant cells (24). Multidrug resistance-associated protein 1 (MRP1) is another classic ABC transporters protein that is closely associated with the chemoresistance in GC. As a MRP1 regulator, the overexpression of Siva-1 could regulate the NF−κB pathway to GC cells escape certain chemotherapies (25).

Figure 1

2.2 Inhibition of cell death

Programmed cell death can eliminate damaged cells or cells that replicate pathogens that are at risk of tumor transformation to maintain homeostasis in the body. These processes include apoptosis, ferroptosis, autophagy, pyroptosis, necrosis and necroptosis (26).

Apoptosis is essential for maintaining homeostasis. There are two pathways of apoptosis (Figure 2). One is that antiapoptotic and proapoptotic proteins interact with mitochondria to activate the mitochondrial pathway (19). The B-cell lymphoma-2 (Bcl-2) family is a pivotal protein in the mitochondrial pathway and regulates mitochondrial outer membrane permeabilization (MOMP). Paclitaxel can reduce the expression of Bcl-2 through direct binding, leading to apoptosis (27). BamH1 A fragment leftward reading frame 1 (BALF1) plays a role in maintaining Bcl-2 protein with anti-apoptotic characteristics stability, leading to cancer progression (28). The combined targeted therapy of pro-apoptotic Bax and anti-apoptotic Bcl-xl is a novel therapeutic strategy to overcome cancer progression and resistance (29). P53 is also a classical regulatory gene which can mediate the intrinsic apoptotic pathway (30). The pro-apoptotic protein p53 can be degraded through the exosome miR-769-5p-mediated ubiquitin-proteasome pathway, ultimately leading to cisplatin resistance (31). The other pathway is the extrinsic pathway, in which death receptors on the plasma membrane identify and bind special death ligands, inducing apoptosis (32). As a classical death ligand, tumor necrosis factor (TNF) binds to TNFR1 to recruit downstream molecules, leading to cell apoptotic (33). Studies have shown that TNF-α can regulate the nuclear factor kappa-beta (NF−κB) signaling pathway, driving cisplatin resistance (34).

Figure 2

Autophagy, which is characterized by the self-degradation of intracellular components, plays dual roles in the resistance of GC to chemotherapy and relies on the intensity and duration of the stimuli (Figure 3). In the presence of persistent stimuli, autophagy, known as cytotoxic autophagy, has anticancer effects (35). However, autophagy, which is regulated by multiple proteins and signaling pathways, is also known as cytoprotective autophagy and can promote cancer cell resistance to chemotherapeutic agents (36, 37). Enhanced autophagy was activated by annexin A1 (ANXA1) via the PI3K/Akt pathway, resulting in oxaliplatin resistance in GC. Moreover, knockdown of ANXA1 could restore sensitivity to oxaliplatin (38). METase could inhibit autophagy through regulating the highly up-regulated in liver cancer (HULC)/Forkhead box protein M1 (FoxM1) pathway and enhance resistant cell sensitivity to cisplatin (39). Studies had shown that MFAP2 could promote autophagy and increase the resistance to cisplatin in GC, but the specific mechanism was not yet clear (40). so MEAP2 could be a potential therapeutic targe. As an essential deubiquitinase, USP13 maintained the stability of autophagy-related protein 5 (ATG5) to enhance autophagy and promoted imatinib resistance in cancer cells (41).

Figure 3

Ferroptosis is a unique iron-dependent mode of nonapoptotic regulated cell death, that involves iron-mediated accumulation of reactive oxygen species (ROS), oxidative stress and dysfunction of antioxidative defense (42) (Figure 3). Compared to GC cells, cisplatin-resistant GC cells exhibit lower levels of ferroptosis, evident by lower ROS, malondialdehyde (MDA) and lipid peroxidation and higher intracellular glutathione (GSH) levels (43). ATF3 blocked the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) axis and induced ferroptosis, consequently restoring GC sensitivity to cisplatin. DNAJC12 had been shown to induce doxorubicin resistance through activating the Akt signal to repress cell ferroptosis (44). Cells subjected to continual chemotherapy often resist apoptosis but are sensitive to ferroptosis (45). So ferroptosis induction is considered a potential way to overcome chemoresistance.

2.3 Enhanced DNA damage repair

The DNA damage response (DDR) is a special repair system used to maintain genetic stability and integrity under stress conditions. Targeting DNA damage represents a primary mechanism employed by numerous chemotherapy agents (46). However, certain cancer cells can acquire drug-resistant phenotypes through the enhancement of DNA repair processes. Some nucleotide excision repair (NER) proteins are overexpressed in Pt-resistant cells. Spontaneous NER is one of the significant causes of platinum resistance. Poly (ADP-Ribose) polymerase 1 (PARP1), as an enzyme crucial for repairing DNA damage, can effectively repair damaged DNA by mediating abnormal activation of the base excision repair (BER) pathway, thereby resulting in oxaliplatin resistance (47). The excision repair cross-complementing gene (ERCC) is also a key gene involved in DNA repair. The overexpression of ERCC4 and ERCC3 may confer resistance to cisplatin by part of a mechanism involving the NER pathway (48). The high expression of ERCC1 is strongly associated with the risk of cisplatin in GC and is considered an independent predictor of the efficacy of platinum chemotherapy (49). The expression levels of ERCC1 and ERCC4 are inversely correlated with miR-138-5p in GC samples. Upon silencing miR-138-5p, the upregulation of ERCC1 and ERCC4 occurs, which subsequently reduces the sensitivity of GC cells to cisplatin (50).

2.4 Modulation of the tumor microenvironment

The cellular environment in which tumors exist is referred to as TME, which comprises stromal cells, immune cells, and extracellular components and plays an essential role in tumor progression, drug resistance, and immune escape (Figure 4). Studies have found that the cancer-associated fibroblasts (CAFs) within the GC can secrete stromal cell-derived factor-1 (SDF-1) by activating the Hippo pathway, thereby inducing resistance to 5-Fu (51). Tumor-associated macrophages (TAMs) with the M2 phenotype are also one of the main causes of drug resistance. CXCL5 derived from M2-TAMs induces 5-Fu resistance by regulating the PI3K/Akt/mTOR pathway (52). It’s widely believed that mesenchymal stem cells (MSCs) can mediate the PD-L1, thus leading to GC invasion, metastasis and therapy escape. Wang et al. found MSCs could enhance cisplatin resistance of GC cells exposed to cisplatin through regulating PD-L1 to promote the expression of multi-drug resistance 1 (MDR1) and Reds1 (53). For noncellular components, approximately 50–60% of locally advanced solid tumors show areas of hypoxia. As an important gene of hypoxia, the high expression of HIF-1α can mediate cellular resistance to cisplatin and paclitaxel (54, 55). Regarding trace elements, the levels of zinc, and manganese in GC tissues are markedly higher compared to those in adjacent normal tissues (56).

Figure 4

2.5 Intensification of epithelial-mesenchymal transition

EMT refers to the process of phenotypic transformation of epithelial-like cells into mesenchymal cells. After EMT, cancer cells lose epithelial characteristics and acquire higher migration and transfer ability (57). EMT is involved in several signaling pathways which include the Notch, Wnt, and TGF-β signaling pathways (58). At the molecular level, the changes in a variety of cell adhesion molecules, such as E-cadherin and N-cadherin, indicate the occurrence of EMT. Resistant cells are apt to metasize. The expression level of Ras-related protein 31 (Rab31) is negatively correlated with the sensitivity of cisplatin to stomach adenocarcinoma, and it can activate Twist1 through regulating the Stats/Mucin 1 (MUC-1) signaling, thereby mediating cisplatin resistance and metastasis (59). Liu et al. pointed out that the overexpression of Wilms tumor 1 associated protein (WTAP) was significantly correlated with poor cancer prognosis, as it facilitated the EMT in GC cells by modulating TGF-β expression and stability of mRNA, consequently leading to multiple chemotherapy resistance and metastasis (60). Adenosine deaminases acting on RNA1 (ADAR1) has been shown to be involved in occurrence and development of GC, and it regulates the protein expression levels of EMT-related markers via the antizyme inhibitor1 (AZIN1) pathway. Knockout of ADAR1 can inhibit the metastatic, as well as enhance sensitivity to cisplatin (61).

2.6 Cancer stem cell

Although only a small proportion of GC cells, GC stem cells (gCSCs) are considered the key contributor to tumor initiation, metastasis, recurrence and treatment failure. gCSCs can develop drug resistance by affecting drug efflux, apoptosis, DNA damage repair, TME and EMT, as well as proliferate after escaping chemotherapy, eventually resulting in tumor recurrence and metastasis (62) (Figure 5). As a highly expressed gene in resistant cells, PRKA kinase anchor protein 8L (AKAP-L8) can promote GC cells to acquire stem cell-like features by maintaining the stability of Stearoyl-CoA desaturase 1 (SCD1) via an IGF2 mRNA binding protein 1 (IGF2BP1)-dependent manner, resulting in resistance to oxaliplatin (63). Ukai et al. also found that KH domain-containing RNA-binding signal transduction-associated protein 3 (KHDRBS3) might play a role in stem cell-like characteristics by mediating CD44 variant expression, thereby reducing the sensitivity of GC cells to 5-Fu (64). Metallothionein 1 M (MT1M) plays a key role in tumor progression and formation, and its expression is positively correlated with clinical prognosis. The overexpression of MT1M can inhibit stem cell characteristics and reverse 5-Fu resistance by targeting Glioma-associated oncogene homolog 1 (GLI1) and affecting GLI1 ubiquitination (65). Wnt1 has been proven to be a potential therapeutic target. Tan et al. found the Wnt1-SOX4 positive feedback loop could maintain gCSCs self-renewal and tumorigenicity and associate with the resistance of 5-Fu and oxaliplatin (66).

Figure 5

2.7 Metabolic reprogramming

Metabolic reprogramming of cancer cells can efficiently obtain and utilize nutrients to adapt to various signals of TME and facilitate survival, proliferation and drug resistance. Therefore, it may be a foundation for the development of drug resistance. Cancer cells preferentially produce energy through glycolysis rather than oxidative phosphorylation, the phenomenon referred to as aerobic glycolysis. Xu et al. found that Far upstream element-binding protein 1 (FUBP1), which is involved in regulation of target gene transcriptional in vivo, could positively correlate with aerobic glycolysis and induce oxaliplatin resistance by regulating glycolysis in GC cells (67). He et al. pointed out that pyrimidine biosynthesis could accelerate glycolysis via activating Notch signaling and enhancing the expression of c-Myc, leading to hindering the efficacy of chemotherapy (68). Maintenance complex component 10 (MCM10) is also observed to be enriched in the glycolysis-related pathway, leading to an enhancement of stemness characteristics in GC cells and contributing to paclitaxel resistance (69). Glucose-regulated protein 75 (GRP75) is highly expressed in cisplatin-resistant GC cells. Knockdown of GRP75 can alter the metabolic reprogramming through blocking anti-oxidation/apoptosis-related progress, thereby enhancing the sensitivity to cisplatin (70).

2.8 Non-coding RNAs and exosomes

Non-coding RNAs, involved in miRNAs, lncRNAs, and circRNAs, and exosomes have been extensively studied for their roles in the chemoresistance of GC. Circ_0006089 is highly expressed in GC-resistant cells, while it can induce GC cells resistant to oxaliplatin through mediating Neuropilin 1 (NRP1) expression via sponging miR-217 (71). Fei et al. pointed out that circ_0008315 could accelerate GC progression and hinder therapeutic efficacy of cisplatin by enhancing GC cell stemness property (72). Overexpression of miR-30c-5p can directly target the 3’UTR of Lactate Dehydrogenase A (LDHA) to block glycolysis, thereby reversing resistance (73). The levels of regulator of reprogramming (ROR) and high mobility group protein. A2 (HMGA2) are significantly upregulated, but miR-519d-3p is downregulated in GC tissues and cells. Knocking down ROR can restrain cisplatin resistance in GC cells through targeting miR-519d-3p (74). Chen et al. found that the exosomal circ-0091741 can induce apoptosis and oxaliplatin resistance through blocking miR-330-3p combination with tripartite motif 14 (TRIM14) and activating the Wnt/β-catenin signaling via stabilizing dishevelled 2 (Dvl2) (75).

3 TCM in the treatment of GC

It is well known that active ingredients extracted from Chinese herbs have therapeutic effects on GC. Artemisinin, which is the active ingredient extracted from the leaves and roots of Artemisia annua, is frequently used to cure malaria. In recent years, artemisinin and its derivatives have been shown in numerous investigations to have anticancer properties (76). In both cellular and mouse models, the derivative dihydroartemisinin successfully suppressed tumor progression and vasculogenic mimicry formation (77). Moreover, the combination of dihydroartemisinin and anlotinib can increase the rate of apoptosis and prevent angiogenesis, migration, and invasion of cells (78). Li et al. have discovered that after dihydroartemisinin treatment, E-cadherin showed high expression, while vimentin, Akt, p-Akt, and Snail showed low expression in SGC7901 cells, thereby effectively blocking EMT and inducing cell apoptosis (79). As another derivative, artesunate has been shown to induce apoptosis by downregulating Cox-2 expression and impeding mitochondrial function (80). Su et al. have found that artesunate, dihydroartemisinin, and artemisinin could effectively reduce the incidence of GC in mouse models and prevent the occurrence of Helicobacter pylori-induced GC (81).

As a natural flavonoid, quercetin is the primary active ingredient in Chinese herbs such as hawthorn, licorice, and knotweed, and it has anticancer effects. Through network pharmacology, quercetin is involved in regulating apoptosis, proliferation, metabolism, and oxidative stress of GC and treating GC through PI3K/Akt signaling, EGFR tyrosine kinase inhibitor resistance, Rap1 signaling, ErbB signaling, FoxO signaling, and Ras signaling pathways (82). According to Shen et al., quercetin could inhibit the progression of GC by blocking the PI3K/Akt pathway and inducing mitochondria-dependent apoptosis (83). Ding et al. have discovered that through targeted inhibition of SLC1A5 expression, quercetin could also hasten iron precipitation in GC cells, leading to ferroptosis (84). Additionally, quercetin can upregulate pyroptosis-related genes (GSDMD, GSDME, cleaved CASP1, NLRP3) and activate the pyroptosis pathway to suppress cell proliferation (85).

A variety of natural active ingredients derived from the Chinese herb Salvia miltiorrhiza play an important role in the adjuvant treatment of GC. Tanshinone II can induce ferroptosis and inhibit cell proliferation in BGC803 and NCI-H87 cells by increasing lipid peroxidation and upregulating the expression of ferroptosis markers Ptgs2 and Chac1 (86). Huo et al. also found that tanshinone II could promote apoptosis (87). According to Xiao et al., tanshinone I could effectively induce cell ferroptosis (88). Moreover, tanshinone I can reduce inflammation and inhibit precancerous lesions of GC by reversing abnormal expression of E-cadherin and N-cadherin (89). Another ingredient, diterpenoid tanshinones, has been proven to regulate the expression of angiogenic factors and inhibit tumor angiogenesis (90). Wang et al. have found that a neutral polysaccharide fraction (SMPA) prepared from the roots of Salvia miltiorrhiza could be used as a potential immunomodulator. It improved the TME, stimulated splenocyte proliferation, promoted anti-inflammatory cytokine production, and augmented the killing activity of natural killer cells and cytotoxic T lymphocytes in GC rats (91).

Astragalus IV is one of the active ingredients of Astragalus, which has anti-inflammatory, hypoglycemic, antifibrotic, and anticancer activities (92). Zhu et al. discovered that Astragalus IV could dramatically lower GC cell invasion and migration through reversing TGF-b1-induced EMT (93). Astragalus IV has also been shown to be able to reshape TME and correct CAFs dysfunction caused by dysregulation of mic RNA expression, thereby inhibiting GC cell proliferation, invasion, and migration (94). For precancerous lesions of gastric cancer, Astragalus IV provides therapeutic effects. Zhang et al. discovered that the PLGC rats’ stomach epithelial dysplasia area decreased and their epithelial cells became more symmetrical after Astragalus IV therapy (95). Astragalus saponins can inhibit angiogenesis. In GC cells treated with Astragalus saponins, VEGF, MMP-9, and MMP-3 levels decreased significantly, and the cells stopped in the G2/M stage, thus inhibiting tumor development and invasion (96). Calycosin, as another active ingredient of Astragalus, promotes apoptosis through mediating ROS, thus playing an anticancer role (97). In addition, Li et al. found that calycosin could also improve IM, dysplasia, and protect the stomach in MNNG-induced PLGC rats (98).

Curcumin is a polyphenolic compound derived from turmeric, which has broad-spectrum anticancer effects. The activity and migration of GC cells treated with curcumin decreased in a concentration-dependent manner, which may be related to down-regulating the expression of related genes in the PI3K pathway (99). Curcumin can also inhibit GC cell proliferation by activating P53 and induce apoptosis and autophagy (100).

4 Potential targets and mechanisms of action

4.1 PI3K/Akt signaling pathway

The PI3K/Akt signaling pathway is one of the vital intracellular signaling pathways (Figure 6). PI3K, as a classic lipid kinase, participates in various cellular functions, including growth, proliferation, differentiation, and survival. PI3K can be activated, turning into PI3K-phosphorylated phosphatidylinositol 3,4,5-trisphosphate (PIP3), when stimulated by extracellular signals, such as EGFR, PDGF, RGF, and IGF, thereby promoting signal transduction cascades (101, 102). Akt, which is the most important downstream target, directly responses to PIP3, resulting in regulating downstream effectors (103). The PI3K/Akt signaling pathway is considered a significant cause of chemoresistance in cancer therapy. By controlling key apoptosis factors, including XIAP and the Bcl-2 family, the PI3K/Akt pathway prevents apoptosis and eventually results in chemoresistance. According to numerous studies, overactivation of Akt stimulates Bcl-2 while inhibiting Bax, thereby promoting cancer cell survival (104). Liu et al. demonstrated that overactivation of the PI3K/Akt signaling pathway upregulated the expression of Bcl-2 in cancer cells and significantly inhibited cisplatin-induced apoptosis (105). As a primary apoptosis inhibitor, XIAP can bind to caspase-9 and caspase-3 to block active caspase and inhibit apoptosis. In parts of cancer cells, XIAP is highly expressed, which is thought to be related to drug resistance. XIAP, which is downstream of Akt, upregulates the PI3K/Akt cell survival signaling pathway to prevent apoptosis (106). In addition, abnormal activation of the PI3K/Akt pathway mediates the expression of ABC transporters, which increases drug efflux and reduces drug response through up-regulation of P-gp, BCRP, and MRP1 expressions, thus leading to chemoresistance (107). The metabolic reprogramming of cancer cells to increase energy supply during chemotherapy is one of the causes of drug resistance. As an important regulator of glucose metabolism, Dong et al. found that through ROS-mediated activation of the PI3K/Akt signaling pathway, HIF-1α was up-regulated in cancer cells, inducing glucose metabolic reprogramming, and eventually cancer cells acquire resistance to anti-tumor drug (108). Consequently, targeting the PI3K/Akt signaling pathway may play a pivotal role in overcoming chemoresistance.

Figure 6

Research had demonstrated that quercetin may successfully cause chemosensitization and reverse MDR. Through network pharmacology and molecular docking studies, Guo et al. demonstrated that the reversal of MDR by quercetin was closely associated with the PI3K/Akt signaling pathway (109). Following additional investigation, it was found that the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is concentration-dependently upregulated in quercetin-treated KATOIII/OXA cell lines, which blocked the phosphorylation of the PI3K/Akt signaling pathway, limited P-gp activity, and increased the intracellular level of oxaliplatin in KATOIII/OXA cells, thereby reversing oxaliplatin resistance (110). As an active component of celastrus and triperygium, celastrol exhibits significant broad-spectrum anticancer activities for the treatment of various cancers. Zhan et al. investigated the impact of celastrol on the PI3K/Akt signaling pathway and the expression levels of related proteins in the SGC7901/DDP cell line. Their findings indicated a significant reduction in the expressions of p-PI3K, p-mTOR, and p-4EBP1 in the SGC7901/DDP cells treated with celastrol, leading to PI3K/Akt signaling pathway inhibition. Additionally, the combination of celastrol and cisplatin reduced the expression of P-gp and MRP1 in the SGC7901/DPP cells. Therefore, celastrol was shown to reverse cisplatin resistance by inhibiting PI3K/Akt signaling and downregulating drug resistance-related protein expression (111). Zhang et al. had demonstrated that dihydroartemisinin exhibited anti-cancer efficacy in the treatment of SGC7901/DDP cells, and significantly enhanced the levels of autophagy-related proteins such as Beclin-1 and LC3II by inhibiting the PI3K/Akt/mTOR signaling pathway while concurrently downregulated P-gp, thereby increasing sensitivity to cisplatin (112). Ginsenoside Rg3 could both sensitize GC cells to cisplatin-induced cell death and relieve miR-420-mediated cisplatin resistance. The fundamental process might entail that Rg3 enforced SOX2 expression and exerted cytotoxic effects due to the downregulation of SOX2 in AGS/DDP GC cells, resulting in inhibiting downstream PI3K/Akt signaling pathway hyperactivation (113). Jaridon 6, a diterpene derived from Rabdosia rubescens, is thought to have the ability to activate autophagy. According to research by Fu et al., Jaridon 6 could effectively inhibit the proliferation of paclitaxel-resistant cells and 5-Fu-resistant cells both in vivo and in vitro. This may reduce the activity of the sirtuin1 (SIRT1) enzyme via the PI3K/Akt signaling pathway (114). Chen et al. discovered that baicalein could increase the susceptibility of stomach cancer cells to 5-Fu under hypoxic conditions. According to the mechanism study, baicalein could downregulate downstream important glycolytic enzymes (HK2, LDH-A, PDK1) by encouraging the accumulation of intracellular PTEN and inhibiting the activation of the PI3K/Akt signaling, thereby reversing the hypoxia-induced 5-Fu resistance (115). The BGC823 and SGC7901 cell lines treated with berberine had markedly reduced MDR1 and MRP1 expressions. In the meantime, cisplatin resistance was reversed by berberine and cisplatin combination therapy, which suppresses the PI3K/Akt signaling and increases caspase-3 and caspase-9 activation to cause apoptosis (116).

A traditional prescription that demonstrated an enhanced immune response through anti-oxidation and anti-inflammation is the decoction of Buzhong Yiqi (BZYQ). To prevent GC growth and immunological escape, Liu et al. had used modified-BZYQ (mBZYQ), guided by clinical practice and traditional Chinese medicine theory. The levels of PI3K, p-PI3K, and p-AKT in BGC823 cells were decreased after the intervention of mBZYQ, which resulted in activation of T lymphocytes and inhibited the PD-L1 expression in GC. This worked in concert with 5-Fu to prevent the progression of GC (117). The decoction of Jianpi Yangwei (JPYW) could increase the apoptosis of BGC825/5-Fu cells by lowering the p-Akt to Akt ratio, which inhibited the expression of MDR1 and MRP1 while increasing Bcl-2 and caspace-3. Combining JPYW with the pathway inhibitor LY294002 could further reduce MDR1 expression and encourage apoptosis (118).

4.2 NF−κB signaling pathway

The transcription factor a common gene regulator, NF−κB plays a role in the recoding of cell adhesion molecules, cytokines, and cytokine receptors (119). The occurrence and development of tumors, including their proliferation, differentiation, migration, and resistance to radiation and chemotherapy, are intimately linked to aberrant NF−κB activation. The NF−κB family’s REL homology domain regulates DNA binding, dimerization, and interactions with inhibitory factors called IκB proteins (120). NF−κB complexes are found in the cytoplasm of the majority of untransformed cell types. They also prevent nuclear uptake and DNA binding, which results in transcriptional inactivation (121). The IKK complex is made up of the catalytic subunits IKKα and IKKβ as well as the regulatory component IKKγ (NEMO) (122). Following the activation of their respective receptors by signaling molecules, the IKK complex activates and causes the ubiquitin proteasome pathway to hydrolyze NF−κB complexes. This leads to the release of NF−κB dimers from cytoplasmic inhibition and their translocation to the nucleus, which in turn drives transcription of the target gene (123). The NF-kB signaling pathway is also a driving factor for chemoresistance in parts of malignant tumors (Figure 7). After stimulating, the NF-kB pathway may participate in the regulation of P-gp expression through binding to the MDR1 gene promoter region. According to Song et al., Adriamycin-resistant cells exhibited a marked overexpression of P-gp and NF-kB signaling pathway, and NF-kB inhibitor BAY1-7082 could overcome drug resistance through blocking the pathway and downregulating P-gp expression (124). Aronia berry extracts had also been demonstrated to reverse gemcitabine resistance, through inhibiting the NF-kB pathway in Pancreatic ductal adenocarcinoma (PDAC) cells to target the expressions of MYD88 and P-gp (125). Moreover, it has also been demonstrated that NF-kB pathway is associated with apoptosis, causing the activation of genes linked to anti-apoptosis through target genes, which results in apoptosis escape and reducing drug efficacy. According to one study, MIR55HG could mediate cisplatin and 5-Fu resistance of GC by triggering the NF-kB signaling pathway and preventing cisplatin and 5-Fu-induced apoptosis (126). Yan et al. found that IL-33 could activate the NF-kB signaling pathway, which in turn could downregulate caspase-3 expression, while increase the expressions of Bcl-2 and Bax, leading to reduce the sensitivity of acute myeloid leukemia to chemotherapy (127). The NF-kB pathway also participates in TME-related chemoresistance. CAFs can mediate platinum resistance in GC and PDAC by producing IL-8 and activating the NF-kB pathway (128, 129). It has been demonstrated that the occurrence of EMT is closely related to the NF-κB signaling pathway. Fu et al. found that the NF−κB signaling pathway contributes to cisplatin resistance in GC by promoting CD133-induced EMT (130).

Figure 7

Tanshinone I had been shown to inhibit cervical cancer’s growth and resistance to chemotherapy in a way that was dependent on kirsten rat sarcoma virus oncogene homologue (KRAS) (131). Tanshinone I had been shown by Wang et al. to prevent resistant GC cells from proliferating and spreading. The levels of phospho-IKK-a/b, NF−κB, GSDME-NT, cleaved caspase-8, and cleaved caspase-3 were significantly elevated in BGC823/DDP and SGC7901/DDP cells treated with tanshinone I. This implied that tanshinone I reversed cisplatin resistance by triggering pyroptosis through the signaling pathways of NF-kB and caspase -3/-8. In contrast, when combined with tanshinone I, cisplatin’s anti-tumor activity was enhanced and the growth of GC tumors transplanted subcutaneously in mice was inhibited (132). By inhibiting NF-kB-related genes, parthenolide could increase chemosensitivity to paclitaxel by suppressing NF-κB phosphorylation. In comparison to the group treated with paclitaxel alone, the combination treatment of parthenolide and paclitaxel dramatically inhibited proliferation and promoted apoptosis in MKN45 GC cells. Additionally, in all three GC cell lines, parthenolide tended to have a synergistic antitumor impact when combined with paclitaxel and cisplatin (133). Combined treatment of 5-Fu with celastrol effectively inhibited proliferation and induced apoptosis, which may be related to reducing the expression of IκB kinase and NF-κB, inhibiting the NF-κB P60 subunit, and inhibiting the signaling pathway. 5-Fu at lower concentrations could still exert higher anti-cancer effects; at the same time, the adverse reactions caused by cytotoxicity could be alleviated (134). GC cells’ sensitivity to cisplatin had purportedly been connected to curcumol, a bioactive sesquiterpenoid that was isolated from several plants in the genus curcuma (135). According to Hu et al., curcumol could inhibit the NF-κB pathway, and curcumin-treated GC cells exhibited a large rise in miR-7, which improved the sensitivity of GC to cisplatin. However, downregulation of miR-7 or miR-7 knockdown led to increased NF-κB p65 (RELA) and SNAIL protein levels in GC cells, thereby blocking the sensitizing effects of curcumol (136). Wogonin is a flavonoid compound found in Scutellaria baicalensis Georgi (Huang Qin). According to Zhao et al., wogonin made the human GC cells MGC803 more susceptible to 5-Fu-induced apoptosis. Possible mechanisms included suppression of NF-kB nuclear translocation and I-kB phosphorylation and dihydropyrimidine dehydrogenase (DPD) downregulation to slow down drug metabolism, which boosted the anti-tumor efficacy of low dose 5-Fu in MGC803 cells (137). Curcumin further reduced NF-kB activation and downregulated the expression of downstream anti-apoptotic gene products, including Bcl-2 and Bcl-xl, in the SGC7901 cell line treated with chemotherapeutics (etoposide and doxorubicin). This suggested that curcumin may promote apoptosis and reverse chemoresistance through the NF-kB signaling pathway (138). Wu et al. demonstrated that NF-kB activity in the nuclei of SGC7901 cells was significantly inhibited following treatment with aeoniflorin, indicating that paeoniflorin may promote 5-Fu-induced apoptosis by preventing IkBα phosphorylation and reducing NF-kB nuclear translocation (139).

4.3 Mitogen-activated protein kinases signaling pathway

Protein kinases in the MAPK pathway are continuously activated to transmit a variety of input signals, such as hormones, cytokines, cell growth factors, endogenous stressors, and environmental stimuli (140). This sets off a series of events that support several biological processes. The four cascades that make up the MAPK pathway are extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK), and ERK5 (Figure 8). In the MAPK/ERK pathway, when the transmembrane receptors are activated, the cytoplasmic complexes of growth-factor-receptor bound protein (GRB) 2 and son of sevenless (SOS) are recruited to the inner surface of the cell membrane. From the RTK, the signal is sent to RAS. Then, with SOS’s assistance, RAS–GDP becomes RAS–GTP. Additionally, RAS-GTP functions as a molecular switch that sends signals downward, which causes downstream kinase RAF to be recruited and directly phosphorylated. RAF’s downstream kinase, MEK1/2, additionally catalyzes ERK1/2 (141, 142). The dual phosphorylation of MAP3Ks at the TGY motif is necessary for the activation of both JNK and P38. The most crucial MAP2Ks, MKK4 and MKK7, can be triggered to activate JNK (143). Activated JNK phosphorylates numerous cytoplasmic substrates, including cytoskeletal proteins and mitochondrial proteins like Bcl-2 and Bcl-xl, in addition to controlling a few transcription factors, including c-Jun, c-Fos, ATF-2, AP-1, p53, and Elk. The p38 goes from the cytosol to the nucleus after activation, where they activate downstream transcriptional targets such as PAX6, ETS1, PRAK, MK3, RARα, AP-1, ATF1, and CHO to control cellular processes (144) It is generally believed that overactivation of the MAPK/ERK signaling pathway is positively related to chemoresistance. According to one study, the calcium channel blockers lercanidipine and amlodipine could reverse chemoresistance and increase the doxorubicin sensitivity of GC cells through inhibiting the ERK/MAPK pathway (145). Chen et al. have discovered that after continuously stimulating with vincristine, MGC803 showed a high expression level of P-gp and developed resistance to vincristine. Following the addition of MEK inhibitor PD98059, P-gp level decreased significantly, and drug resistance was reversed (146). However, the JNK and P38 MAPK signaling pathways play a dual role in drug resistance. On the one hand, several chemotherapeutic drugs, such as cyclophosphamide and oxaliplatin, induce apoptosis that is reliant on P38 activation (147). Low et al. discovered that dual-specificity phosphatase 16 (DUSP16) increased drug resistance by preventing the activation of the P38 MAPK pathway and the JNK pathways, which led to reduced Bax accumulation in mitochondria to reduce apoptosis (148). However, under certain conditions, apoptosis resistance can also be mediated by the P38 MAPK pathway and the JNK pathway. According to one study, galectin-1 could promote tumor proliferation and medication resistance by activating the P38 MAPK pathway, which in turn increases the expression of Cox-2, which augments tumor angiogenesis and resistance to apoptosis (149). Prostate cancer cells become resistant to docetaxel-induced apoptosis when p38 is phosphorylated (150). HBV X protein can promote drug resistance and decrease adriamycin-mediated apoptosis by activating the JNK pathway (151).

Figure 8

According to Peng et al., sophoridine could mediate the MAPK signaling pathway, enhance the expression of estrogen-related receptor gamma (ESRRG) to promote β-catenin degradation, and inhibit the repair of double-stranded DNA breaks to caused cell cycle arrest at the G2/M phase, thereby lowering GC cell survival and increasing the efficiency of cisplatin. Because ESRRG was a downstream signaling protein of MAPK pathways, the activation of MAPKs ERK1/2, p38, and JNK1/2 promoted the phosphorylation of β-catenin (152). The tumor-suppressive properties of oridonin, an active compound derived from Rabdosia rubescens, had been demonstrated in various GC cell lines. Oridonin demonstrated the ability to inhibit cell proliferation by blocking cycle progression in the C2/M phase while also activating JNK signaling pathways to induce caspase-dependent apoptosis in the HGC27 cell line. However, JNK inhibitor SP600125 hindered the activation of JNK, leading to decreasing oridonin-mediated apoptosis (153). As a potential chemosensitizer, Hong et al. discovered that wogonin could promote oxaliplatin-induced apoptosis by activating phosphorylation of JNK signaling and raising nitrosative stress to accelerate excessive autophagy, thereby synergistically enhancing the chemotherapeutic impact of oxaliplatin on BGC832 cells in vitro (154). As an active ingredient from Dioscorea zingiberensis C.H. Wright, it has been demonstrated that deltonin exhibited anti-cancer properties against a variety of cancer forms. Yang et al. discovered that deltonin might decrease the expressions of downstream apoptotic genes such Bad, Bid, and Fas by lowering the phosphorylation of P38-MAPK in GC cells. This inhibition was further strengthened when cisplatin was added, suggesting that deltonin may increase GC cells’ susceptibility to cisplatin treatment. Furthermore, by blocking the PI3K/Akt/mTOR signaling pathway, deltonin could also reduce the expression levels of important DNA-repair enzymes, such as Rad51 and murine double minute (MDM)2 (155). It had been demonstrated that ethanol extracted of Scutellaria barbata ESB increased the depolarization of the mitochondrial membrane and the activity of caspase-3 and caspase-9, which caused apoptosis. Additionally, the anti-tumor effect was greatly increased when cisplatin, etoposide, or doxorubicin were coupled with ESB; this may be connected to the MAPK signaling pathway. Furthermore, this impact could be lessened by MAPK inhibitors PD98059(an ERK1/2 inhibitor), SB203580(a p38 inhibitor), or SP600125 (a JNK inhibitor) (156). A scaffold protein called kinase suppressor of Ras 1 controls how the oncogenic mitogen-activated ERK/MAPK signaling cascade is initiated. In cisplatin-treated SGC7901 cells, etoposide-treated SGC7901 cells and cisplatin-resistant SGC7901 cells, Ginkgo biloba extract EGb could suppress proliferation and promote apoptosis by reducing the expression of KSR1, p-KSR1, ERK1/2, and p-ERK1/2. This suggested that EGb not only increased chemotherapy sensitivity but also reversed chemotherapy resistance (157).

4.4 P53 signaling pathway

Unquestionably, p53 is a significant tumor suppressor that contributes to both normal proliferation and the inhibition of tumor growth (Figure 9). The p53 levels are regulated by negative feedback mediated by the E3 ubiquitin ligase MDM2 and its homolog MDMX (158). Signals of cell stress, including DNA damage and carcinogenic stress, cause p53 to become active. To lessen aberrant cell accumulation and stop tumors from forming, it, on the one hand, controls downstream signals, aids in the repair of DNA damage, stops the cell cycle, and transduces the caspase signal through the activation of the mitochondrial pathway or death receptor pathway to promote apoptosis when damage cannot be repaired (159). On the other hand, p53 ubiquitination by MDM2 and MDMX is followed by proteolytic hydrolysis or nuclear export to maintain the stability of the p53 level (160). Continuous stimulation can reduce P53 stability; additionally, mutant p53 is the most prevalent genetic abnormality in cancer cells, which are strongly linked to medication resistance. Di et al. have discovered that after continuous oxaliplatin stimulation, p53 ubiquitination was enhanced and its stability was damaged, thus inducing oxaliplatin resistance in CRC (161). Moreover, continuous temozolomide stimulation could cause P53 to become phosphorylated, which decreased drug absorption and improved DNA damage repair, leading to induced chemoresistance (162). According to Jing et al., miR-769-5p causes cisplatin resistance by promoting p53 degradation and blocking apoptosis via the ubiquitin-proteasome system (31). P53 can also simultaneously enhance cell survival and proliferation and control chemotherapy resistance through triggering various survival signaling pathways, including the NF-kB signaling pathway. Yang et al. have found that P53 could promote NF-kB p65 nuclear translocations in A549 or H358 cell lines, thereby enhancing the cell’s drug resistance to cisplatin and paclitaxel, which was significantly weakened after treatment with the NF-kB inhibitor PS1145 (163).

Figure 9

Xu et al. found that when doxorubicin and tanshinone II were administered together to doxorubicin-resistant SNU719 cells, the levels of p53 and Bax rose while those of Bcl-2 fell. However, doxorubicin alone had virtually no effect on the expression of genes linked to apoptosis. These suggested that via triggering the p53 signaling pathway, tanshinone II could induce apoptosis in doxorubicin-resistant SNU719 cells. Furthermore, it also enhanced the anticancer impact of doxorubicin via inhibition of MRP1 function (164). Because oridonin dramatically increased apoptotic cell and decreased cell viability, it remarkably amplified the anti-tumor impact of cisplatin. According to Bi et al., it increased the level of p53 expression by suppressing MDM2 expression through negative feedback regulation; at the same time, oridonin increased the pro-apoptotic function of p53 by suppressing the expression of anti-apoptotic genes Bcl-2 and up-regulating the expression of genes linked to pro-apoptosis, such as p53, p-p53, p21, and Bax (165). Liquiritin, a key component of licorice flavonoids, could increase cisplatin’s killing capacity and decrease resistance in SGC7901/DDP cells by preventing the cell cycle, triggering apoptosis and promoting autophagy. In the study, liquiritin and cisplatin caused cyclin D1 and cyclin A to all decrease at the same time, further arresting the G1/G0 cell cycle. Moreover, it increased LC3B-II and Beclin 1, which in turn stimulated caspase-8/-9/-3 and PARP cleavage, upregulating apoptosis autophagy (166). Scutellaria baicalensis is a Chinese herb that contains the potent compound baicalin. According to Shao et al., it dramatically rose p53 expression in HGC-27/OXA cells, which in turn targeted downstream ferroptosis activation by blocking SLC7A11 and glutathione peroxidase (GPX) 4 and promoting ROS accumulation, resulting in reverse oxaliplatin resistance (167). Extracted from frankincense, boswellic acid had been demonstrated to increase cisplatin-mediated apoptosis in GC cells by upregulating p53 expression and subsequently decreasing Akt downstream phosphorylation (168). A naturally occurring substance called Genipin, which comes from Gardenia jasminoides, may be a sensitizer to accelerate oxaliplatin-induced cell apoptosis and autophagy. It could trigger p53 expression, which in turn promoted the cleavage of PARP, caspase-9, and caspase-3 and rose damage-regulated autophagy modulator (DRAM) (169). According to Lee et al., Chrysin and 5-Fu worked together to enhance the anticancer effects of 5-Fu and overcame 5-Fu resistance in vitro by further upregulating p53 and subsequently stimulating p21 activity to block arrest in AGS/5-Fu cells (170).

4.5 Signal transducers and activators of transcription 3 signaling pathway

Seven genes have been found by the STAT family; STAT3 in particular is generally thought to be linked to metastasis, cancer growth, and multidrug resistance (171) (Figure 10). The classical STAT3 signaling pathway is activated by a number of growth factors (EGF, FGF, IGF) and cytokines (IL-6, IL-10) binding to their appropriate reporters. The associated janus kinase (JAK) proteins are activated, self-phosphorylated, and transphosphorylate the receptor-associated tyrosine residues (172). Phosphorylated tyrosine residues are bound by STAT3 through its SH2 domain (173, 174). Homodimers are formed by the phosphorylated STAT3. Following its release from the receptors, importins quickly carry the pSTAT-pSTAT dimer into the nucleus. The dimer mediates subsequent biological functions, such as metastasis, cell death and drug resistance, by forming complexes with certain activators and binding to target gene promoters for transcription (175, 176). More and more studies have shown that the STAT3 signaling pathway plays a significant role in the regulation of tumor stemness and EMT, promoting EMT through key regulatory factors and subsequently producing cell stemness and chemoresistance (177). According to Shi et al., Glycochenodeoxycholic acid (GCDC) could reduce E-cadherin expression and enhance vimentin expression by activating the STAT3 pathway and then induce EMT and enhance the development of CSC-like characteristics in HCC cells, resulting in resistance to 5-Fu and cisplatin (178). By controlling metabolism, the STAT3 pathway can also affect cancer cell sensitivity to drugs. In prostate tumors, the activation of STAT3 signaling enhances glycolysis and proliferation in cancer cells, inhibits apoptosis, induces EMT mechanisms to facilitate cancer metastasis, and additionally activates drug resistance pathways (179). Wang et al. have found that the JAK/STAT3 pathway could control the expression of several genes involved in lipid metabolism, such as carnitine palmitoyltransferase 1B (CPT1B) and fatty acid β-oxidation (FAO), to mediate cancer stemness and chemoresistance (180). Chemoresistance could be reversed when FAO is blocked. JAK/STAT3 can also induce chemotherapy resistance in TME via inducing M2 polarization of macrophages (181).

Figure 10

Danshen’s fat-soluble diterpene, crypotanshinone, increased the effectiveness of 5-Fu in a mouse model of GC by reducing P-gp expression and altering the transcriptional activity of the MDR1 gene via the JAK2/STAT3 signaling pathway (182). Additionally, Cao et al. discovered that crypotanshinone reversed 5-Fu resistance and boosted the inhibitory effect of 5-Fu in SGC7901/5-Fu cells by blocking the JAK/STAT3 signaling pathway, which in turn lowed the levels of Mcl-1, Bcl-xl, and Bcl-2 expression while raising Bax expression (183). The anticancer activity of doxorubicin is further enhanced by crypotanshinone, which significantly suppressed constitutive and phosphorylation of STAT3 Tyr705 to inhibit STAT3 activity. This lowed the levels of proteins encoded by downstream target genes (Bcl-xL, Mcl-1, survivin) (184). Schisandrin B could enhance 5-Fu sensitivity in GC cells and cooperate to stop 5-Fu-induced cell death in vitro and in vivo, according to He and colleagues. SchisandrinB may be responsible for controlling STAT3 upstream proteins (SOCS, PIAS, PTPs) which in turn may cause autophagy triggered by STAT3 signaling activation (185). Berberine may be able to target STATs and surviving cells in drug-resistant GC cells, increasing the sensitivity of these cells to 5-Fu (186). Parthenolide-treated SGC7901/DDP cells showed decreased STAT3 activation, which led to apoptosis by raising the expression of Bax, P53, and cleaved caspase-9/-3 protein and lowering that of Bcl-2 and Bcl-x. Therefore, by blocking the STAT3 signaling pathway, parthenolide could reverse cisplatin resistance in GC (187). A decoction of banxia xiexin (BXXX) could lower the expression levels of DNA methyltransferases PD-L1 and O6-methylguanine-DNA methyltransferase (MGMT), which worked through the IL-6/JAK/STAT3 pathway, in GC cells resistant to cisplatin (188). This stops GC from proliferating while intensifying cisplatin’s inhibitory actions. ,

4.6 Other signaling pathway

As a multifunctional cytokine, TGF-β plays a role in immune response, apoptosis, differentiation, and cell proliferation. When the TGF ligand binds to the type II TGF receptor, classical TGF signaling begins. The type I TGF-β receptor is then recruited and phosphorylated, which phosphorylates the transcription factor Smad and starts downstream signal transduction, particularly EMT (189). Recent research has suggested that the TGF-β pathway may play a key role in cancer treatment resistance (190). Isolequiritigenin, which was another natural flavonoid from licorice, prevented GRP78-mediated stemness by suppressing the expression of transcriptional factors (SOX2, Nanog), linked to stemness, and cell surface indicators (CD24, CD44, LGR5). Additionally, it inhibited MMP-9 and IL-6, which prevented CAFs from activating to decrease drug resistance and ultimately boost chemosensitivity to 5-Fu, hence reducing TGF-B release by GC cells (191). By suppressing cancerous inhibitor of PP2A (CIP2A) expression in cells, polyphyllin I counteracted TGF-β1-mediated downregulation of E-cadherin and upregulation of vimentin, indicating that it may prevent EMT-promoted invasion and improve effectiveness when used in conjunction with chemotherapy (192).

Cellular resistance to oxidative damage is regulated by Nrf2, a transcription factor linked to oxidative stress. Nrf2 shields cancerous cells from chemotherapy that results in chemoresistance, as well as healthy cells from ROS-induced DNA damage (193, 194). Le et al. discovered that baicalein might increase the sensitivity of cisplatin in drug-resistant cells by lowering the levels of Nrf2 and Keap1 in SGC7901/DDP cells while also lowering the expression of MDR1. Furthermore, by blocking the Akt/mTOR pathway and upregulating the expression of LC3B and beclin 1, baicalin could cause drug-resistant cells to undergo autophagy and death (195). According to Huang et al., Yi-qi-hua-yu-jie-du (YQHYJD) decoction could reverse 5-Fu resistance and speed up apoptosis. This could partially restrict cell stemness by reducing MDR1 and MRP1 expression by blocking activity of the PI3K/Akt/Nrf2 pathway (196). Glutathione metabolism is frequently dysregulated in cisplatin-resistant GC. Further investigations by Huang et al. had demonstrated that YQHYJD could mitigate cisplatin resistance. The underlying mechanism may involve the inhibition of the phosphorylation cascade activity within the Akt/GSK3β pathway and modulation of Nrf2 expression, thereby reprogramming glutathione metabolism and promoting ferroptosis (197).

The Wnt/β-catenin pathway, sometimes referred to as the classical Wnt pathway, is typically highly conserved and is triggered by extracellular Wnt ligands interacting to membrane receptors (Frizzled, LRP5/6) autocrinely or paracrinely. After activation, the Wnt/β-catenin pathway causes β-catenin to become stable and move to the nucleus, where it uses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors to activate and control downstream target genes, ultimately increasing the expression of genes related to cell migration, differentiation, proliferation, and survival (198, 199). Chemotherapy resistance has been linked to the Wnt/β-catenin signaling pathway in a number of cancers, including GC (200). Hosseini et al. found that cornus officinalis extract could induce apoptosis of GC cell lines and effectively inhibit cell proliferation in vitro (201). Subsequent investigation revealed that loganin, the primary active component of cornus officinals, combined with 5-Fu inhibited the Wnt/β-catenin pathway and reduced the accumulation of β-catenin in the cytoplasm and nucleus, thereby downregulating downstream targets and key proteins to significantly inhibit stem-like properties and migration, suggesting that loganin could be an efficient sensitizer to boost 5-Fu’s anti-tumor effect (202). According to research by Hou et al., cardamonin may enhance the chemosensitivity of the BGC823/5-Fu cell line to 5-Fu by suppressing the expression of Wnt target genes (β-catenin, TCF5) and interfering with the β-catenin/TCF4 complex formation. Moreover, it might promote Rh123 accumulation to prevent P-gp overexpression. Additionally, cardamonin and 5-Fu considerably slowed the growth of tumors in vivo (203). When combined with cisplatin, ginsenoside Rg3 could further decrease SGC7901/DDP cell migration, proliferation, and EMT while promoting cell death. In the meantime, cisplatin and Rg3 could inhibit the expression of associated proteins in the Wnt/β-catenin signaling pathway, suggesting that Rg3 could regulate cisplatin resistance (204).

5 Conclusion

Chemotherapy resistance is still an urgent problem in the treatment of malignant tumors. Intracellular signal pathways are involved in numerous biological processes and have also been demonstrated to be intimately linked to the development of drug resistance. Currently, blockers that target genes or signaling pathways linked to drug resistance have been discovered but are not utilized widely in clinical settings due to high cost and severe side effects. TCM has a lengthy history, a distinct theoretical framework, exceptional clinical effectiveness, and a significant role in the management of cancerous tumors. According to numerous fundamental tests and clinical data conducted in recent years, TCM can be employed as an auxiliary sensitizer of traditional chemotherapy drugs, effectively improve anti-cancer efficacy and reverse chemotherapy resistance. This review summarizes the primary mechanism of GC chemoresistacne and focuses on mechanisms of enhancing chemotherapy sensitivity and reversing drug resistance in TCM from the standpoint of the signaling pathways, which include PI3K/Akt, NF-kB, MAPK, P53, STAT3, TGF-β, Nrf2, and Wnt/b-catenin, thereby affecting various biological processes, such as cell cycle, cell proliferation, migration, apoptosis, autophagy, ferroptosis, TME, EMT, DNA damage repair, and cell stemness (Table 1). Whether TCM is taken alone or in conjunction with other anticancer medications, we think it has a lot of potential as an ongoing and alternative clinical treatment for cancer.

However, there are still certain shortcomings and restrictions in pertinent studies as of right now. Most of the existing studies focus on the role of a single signaling pathway or a single gene, and do not involve the interaction between pathways. In addition, the current research on the pharmacological mechanism of TCM mostly focuses on in vitro cell experiments, lacking a dearth of adequate and trustworthy in vivo experimental results as well as clinical efficacy data. TCM has the characteristics of multi-components and multi-targets, and the same monomer may affect multiple targets, which is incompatible with the concept of accurate targeted therapy in modern medicine. The use of the TCM formulas should be based on the treatment with syndrome differentiation, which is one of the features of TCM theoretical system; however, at the moment, nearly all research does not include the syndrome differentiation. Lastly, the extraction and clinical application of active components present additional challenges, including increasing drug extraction rate, increasing drug concentration, maintaining drug stability, improving bioavailability, and pharmacokinetics.

This review aims to present a new theoretical foundation for overcoming chemotherapy resistance in GC, as well as ideas for the development of new chemotherapy sensitizers and a favorable research direction, in order to provide a better, safer and more effective treatment plan and drug selection for enhancing the anti-tumor effect of traditional chemotherapy drugs and reversing chemotherapy resistance in the future.

References

• 1

  BrayFLaversanneMSungHFerlayJSiegelRLSoerjomataramIet al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2024) 74:229–63. doi: 10.3322/caac.21834

  • CrossRef
  • Google Scholar

• 2

  SmythECNilssonMGrabschHIvan GriekenNCLordickF. Gastric cancer. Lancet. (2020) 396:635–48. doi: 10.1016/S0140-6736(20)31288-5

  • CrossRef
  • Google Scholar

• 3

  AjaniJAD'AmicoTABentremDJChaoJCookeDCorveraCet al. Gastric cancer, version 2. 2022 NCCN Clin Pract Guidelines Oncol J Natl Compr Canc Netw. (2022) 20:167–92. doi: 10.6004/jnccn.2022.0008

  • CrossRef
  • Google Scholar

• 4

  Al-BatranSEHartmannJTProbstSSchmalenbergHHollerbachSHofheinzRet al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. (2008) 26:1435–42. doi: 10.1200/JCO.2007.13.9378

  • CrossRef
  • Google Scholar

• 5

  GuimbaudRLouvetCRiesPYchouMMaillardEAndréTet al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol. (2014) 32:3520–6. doi: 10.1200/JCO.2013.54.1011

  • CrossRef
  • Google Scholar

• 6

  MoehlerMKanzlerSGeisslerMRaedleJEbertMPDaumSet al. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. (2010) 21:71–7. doi: 10.1093/annonc/mdp269

  • CrossRef
  • Google Scholar

• 7

  BangYJVan CutsemEFeyereislovaAChungHCShenLSawakiAet al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. (2010) 376:687–97. doi: 10.1016/S0140-6736(10)61121-X

  • CrossRef
  • Google Scholar

• 8

  JanjigianYYKawazoeABaiYXuJLonardiSMetgesJPet al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. (2023) 402:2197–208. doi: 10.1016/S0140-6736(23)02033-0

  • CrossRef
  • Google Scholar

• 9

  JanjigianYYShitaraKMoehlerMGarridoMSalmanPShenLet al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. (2021) 398:27–40. doi: 10.1016/S0140-6736(21)00797-2

  • CrossRef
  • Google Scholar

• 10

  FuchsCSTomasekJYongCJDumitruFPassalacquaRGoswamiCet al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. (2014) 383:31–9. doi: 10.1016/S0140-6736(13)61719-5

  • CrossRef
  • Google Scholar

• 11

  WilkeHMuroKVan CutsemEOhSCBodokyGShimadaYet al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. (2014) 15:1224–35. doi: 10.1016/S1470-2045(14)70420-6

  • CrossRef
  • Google Scholar

• 12

  KimCGJungMKimHSLeeCKJeungHCKooDHet al. Trastuzumab combined with ramucirumab and paclitaxel in patients with previously treated human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer. J Clin Oncol. (2023) 41:4394–405. doi: 10.1200/JCO.22.02122

  • CrossRef
  • Google Scholar

• 13

  FordHEMarshallABridgewaterJAJanowitzTCoxonFYWadsleyJet al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. (2014) 15:78–86. doi: 10.1016/S1470-2045(13)70549-7

  • CrossRef
  • Google Scholar

• 14

  KawamotoYYukiSSawadaKNakamuraMMutoOSogabeSet al. Phase II study of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with advanced gastric cancer: HGCSG1603. Oncologist. (2022) 27:e642–e9. doi: 10.1093/oncolo/oyac086

  • CrossRef
  • Google Scholar

• 15

  ShitaraKDoiTDvorkinMMansoorWArkenauHTProkharauAet al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2018) 19:1437–48. doi: 10.1016/S1470-2045(18)30739-3

  • CrossRef
  • Google Scholar

• 16

  RamosASadeghiSTabatabaeianH. Battling chemoresistance in cancer: root causes and strategies to uproot them. Int J Mol Sci. (2021) 22(17):9451. doi: 10.3390/ijms22179451

  • CrossRef
  • Google Scholar

• 17

  XuJFWanYTangFChenLYangYXiaJet al. Emerging significance of ginsenosides as potentially reversal agents of chemoresistance in cancer therapy. Front Pharmacol. (2021) 12:720474. doi: 10.3389/fphar.2021.720474

  • CrossRef
  • Google Scholar

• 18

  NewmanDJCraggGM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. (2016) 79:629–61. doi: 10.1021/acs.jnatprod.5b01055

  • CrossRef
  • Google Scholar

• 19

  AssarafYGBrozovicAGonçalvesACJurkovicovaDLinēAMachuqueiroMet al. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat. (2019) 46:100645. doi: 10.1016/j.drup.2019.100645

  • CrossRef
  • Google Scholar

• 20

  WuJZhouZLiJLiuHZhangHZhangJet al. CHD4 promotes acquired chemoresistance and tumor progression by activating the MEK/ERK axis. Drug Resist Updat. (2023) 66:100913. doi: 10.1016/j.drup.2022.100913

  • CrossRef
  • Google Scholar

• 21

  WangSGuoJMoZShiXQuC. Clinical significance and correlation of miR-200c and P-gp expression in gastric cancer and the effects on multidrug resistance. J Gastrointest Oncol. (2022) 13:581–92. doi: 10.21037/jgo-22-167

  • CrossRef
  • Google Scholar

• 22

  WuLCaiSDengYZhangZZhouXSuYet al. PD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression. Int Immunopharmacol. (2021) 94:107443. doi: 10.1016/j.intimp.2021.107443

  • CrossRef
  • Google Scholar

• 23

  XuEZhuHWangFMiaoJDuSZhengCet al. OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction. Curr Mol Med. (2021) 21:922–30. doi: 10.2174/1566524020666201120113538

  • CrossRef
  • Google Scholar

• 24

  LuoJYuanJYangYJiangYYanJTongQ. Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters. Cancer Sci. (2023) 114:1353–64. doi: 10.1111/cas.v114.4

  • CrossRef
  • Google Scholar

• 25

  KongFBDengQMDengHQDongCCLiLHeCGet al. Siva−1 regulates multidrug resistance of gastric cancer by targeting MDR1 and MRP1 via the NF−κB pathway. Mol Med Rep. (2020) 22:1558–66. doi: 10.3892/mmr.2020.11211

  • CrossRef
  • Google Scholar

• 26

  BedouiSHeroldMJStrasserA. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. (2020) 21:678–95. doi: 10.1038/s41580-020-0270-8

  • CrossRef
  • Google Scholar

• 27

  KwonCHParkHJChoiYWonYJLeeSJParkDY. TWIST mediates resistance to paclitaxel by regulating Akt and Bcl-2 expression in gastric cancer cells. Tumour Biol. (2017) 39:1010428317722070. doi: 10.1177/1010428317722070

  • CrossRef
  • Google Scholar

• 28

  LinHHanYSangYWuYTianMChenXet al. OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2. Biochim Biophys Acta Mol Basis Dis. (2024) 1870:167132. doi: 10.1016/j.bbadis.2024.167132

  • CrossRef
  • Google Scholar

• 29

  LopezAReynaDEGitegoNKoppFZhouHMiranda-RomanMAet al. Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer. Nat Commun. (2022) 13:1199. doi: 10.1038/s41467-022-28741-7

  • CrossRef
  • Google Scholar

• 30

  YuYQThonnVPatankarJVThomaOMWaldnerMZielinskaMet al. SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth. Cell Death Dis. (2022) 13:52. doi: 10.1038/s41419-021-04483-0

  • CrossRef
  • Google Scholar

• 31

  JingXXieMDingKXuTFangYMaPet al. Exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. Clin Transl Med. (2022) 12:e780. doi: 10.1002/ctm2.v12.5

  • CrossRef
  • Google Scholar

• 32

  Ketelut-CarneiroNFitzgeraldKA. Apoptosis, pyroptosis, and necroptosis-oh my! The many ways a cell can die. J Mol Biol. (2022) 434:167378. doi: 10.1016/j.jmb.2021.167378

  • CrossRef
  • Google Scholar

• 33

  SeyrekKIvanisenkoNVRichterMHillertLKKönigCLavrikIN. Controlling cell death through post-translational modifications of DED proteins. Trends Cell Biol. (2020) 30:354–69. doi: 10.1016/j.tcb.2020.02.006

  • CrossRef
  • Google Scholar

• 34

  de CastroLRde OliveiraLDMilanTMEskenaziAPEBighetti-TrevisanRLde AlmeidaOGGet al. Up-regulation of TNF-alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma. J Cell Physiol. (2024) 239:e31164. doi: 10.1002/jcp.v239.2

  • CrossRef
  • Google Scholar

• 35

  Muñoz-GuardiolaPCasasJMegías-RodaESoléSPerez-MontoyoHYeste-VelascoMet al. The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. (2021) 17:1349–66. doi: 10.1080/15548627.2020.1761651

  • CrossRef
  • Google Scholar

• 36

  XuJLYuanLTangYCXuZYXuHDChengXDet al. The role of autophagy in gastric cancer chemoresistance: friend or foe? Front Cell Dev Biol. (2020) 8:621428. doi: 10.3389/fcell.2020.621428

  • CrossRef
  • Google Scholar

• 37

  Zamame RamirezJARomagnoliGGKanenoR. Inhibiting autophagy to prevent drug resistance and improve anti-tumor therapy. Life Sci. (2021) 265:118745. doi: 10.1016/j.lfs.2020.118745

  • CrossRef
  • Google Scholar

• 38

  RenJHuZNiuGXiaJWangXHongRet al. Annexin A1 induces oxaliplatin resistance of gastric cancer through autophagy by targeting PI3K/AKT/mTOR. FASEB J. (2023) 37:e22790. doi: 10.1096/fj.202200400RR

  • CrossRef
  • Google Scholar

• 39

  XinLZhouQYuanYWZhouLQLiuLLiSHet al. METase/lncRNA HULC/FoxM1 reduced cisplatin resistance in gastric cancer by suppressing autophagy. J Cancer Res Clin Oncol. (2019) 145:2507–17. doi: 10.1007/s00432-019-03015-w

  • CrossRef
  • Google Scholar

• 40

  LiMZhangHYZhangRG. MFAP2 enhances cisplatin resistance in gastric cancer cells by regulating autophagy. PeerJ. (2023) 11:e15441. doi: 10.7717/peerj.15441

  • CrossRef
  • Google Scholar

• 41

  GaoZLiCSunHBianYCuiZWangNet al. N(6)-methyladenosine-modified USP13 induces pro-survival autophagy and imatinib resistance via regulating the stabilization of autophagy-related protein 5 in gastrointestinal stromal tumors. Cell Death Differ. (2023) 30:544–59. doi: 10.1038/s41418-022-01107-8

  • CrossRef
  • Google Scholar

• 42

  ZhangRKangRTangD. Ferroptosis in gastrointestinal cancer: from mechanisms to implications. Cancer Lett. (2023) 561:216147. doi: 10.1016/j.canlet.2023.216147

  • CrossRef
  • Google Scholar

• 43

  FuDWangCYuLYuR. Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling. Cell Mol Biol Lett. (2021) 26:26. doi: 10.1186/s11658-021-00271-y

  • CrossRef
  • Google Scholar

• 44

  ShenMCaoSLongXXiaoLYangLZhangPet al. DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT. Redox Biol. (2024) 70:103035. doi: 10.1016/j.redox.2024.103035

  • CrossRef
  • Google Scholar

• 45

  WangYWuXRenZLiYZouWChenJet al. Overcoming cancer chemotherapy resistance by the induction of ferroptosis. Drug Resist Updat. (2023) 66:100916. doi: 10.1016/j.drup.2022.100916

  • CrossRef
  • Google Scholar

• 46

  SethyCKunduCN. 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. BioMed Pharmacother. (2021) 137:111285. doi: 10.1016/j.biopha.2021.111285

  • CrossRef
  • Google Scholar

• 47

  LiHWangCLanLYanLLiWEvansIet al. METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability. Cell Mol Life Sci. (2022) 79:135. doi: 10.1007/s00018-022-04129-0

  • CrossRef
  • Google Scholar

• 48

  LiMGaoMXieXZhangYNingJLiuPet al. MicroRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway. Oncol Lett. (2019) 18:145–52. doi: 10.3892/ol.2019.10304

  • CrossRef
  • Google Scholar

• 49

  YehYSChenYTTsaiHLHuangCWMaCJSuWCet al. Predictive value of ERCC1, ERCC2, and XRCC expression for patients with locally advanced or metastatic gastric cancer treated with neoadjuvant mFOLFOX-4 chemotherapy. Pathol Oncol Res. (2020) 26:1105–16. doi: 10.1007/s12253-019-00666-5

  • CrossRef
  • Google Scholar

• 50

  NingJJiaoYXieXDengXZhangYYangYet al. miR−138−5p modulates the expression of excision repair cross−complementing proteins ERCC1 and ERCC4, and regulates the sensitivity of gastric cancer cells to cisplatin. Oncol Rep. (2019) 41:1131–9. doi: 10.3892/or.2018.6907

  • CrossRef
  • Google Scholar

• 51

  YangYMaYYanSWangPHuJChenSet al. CAF promotes chemoresistance through NRP2 in gastric cancer. Gastric Cancer. (2022) 25:503–14. doi: 10.1007/s10120-021-01270-w

  • CrossRef
  • Google Scholar

• 52

  SuPJiangLZhangYYuTKangWLiuYet al. Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer. Cancer Cell Int. (2022) 22:290. doi: 10.1186/s12935-022-02717-5

  • CrossRef
  • Google Scholar

• 53

  WangQHuangCWangDTaoZZhangHZhaoYet al. Gastric cancer derived mesenchymal stem cells promoted DNA repair and cisplatin resistance through up-regulating PD-L1/Rad51 in gastric cancer. Cell Signal. (2023) 106:110639. doi: 10.1016/j.cellsig.2023.110639

  • CrossRef
  • Google Scholar

• 54

  SunXPDongXLinLJiangXWeiZZhaiBet al. Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer. FEBS J. (2014) 281:115–28. doi: 10.1111/febs.2013.281.issue-1

  • CrossRef
  • Google Scholar

• 55

  FushidaSOkazakiMKinoshitaJYamaguchiTOhtaT. Impact of HIF-1alpha and PKM1 expression on acquisition of paclitaxel resistance in gastric cancer. Ann Oncol. (2018) 29:v5. doi: 10.1093/annonc/mdy151.015

  • CrossRef
  • Google Scholar

• 56

  SohrabiMNikkhahMSohrabiMRezaee FarimaniAMirasgari ShahiMZiaieHet al. Evaluating tissue levels of the eight trace elements and heavy metals among esophagus and gastric cancer patients: A comparison between cancerous and non-cancerous tissues. J Trace Elem Med Biol. (2021) 68:126761. doi: 10.1016/j.jtemb.2021.126761

  • CrossRef
  • Google Scholar

• 57

  PastushenkoIBlanpainC. EMT transition states during tumor progression and metastasis. Trends Cell Biol. (2019) 29:212–26. doi: 10.1016/j.tcb.2018.12.001

  • CrossRef
  • Google Scholar

• 58

  ChoESKangHEKimNHYookJI. Therapeutic implications of cancer epithelial-mesenchymal transition (EMT). Arch Pharm Res. (2019) 42:14–24. doi: 10.1007/s12272-018-01108-7

  • CrossRef
  • Google Scholar

• 59

  ChenKXuJTongYLYanJFPanYWangWJet al. Rab31 promotes metastasis and cisplatin resistance in stomach adenocarcinoma through Twist1-mediated EMT. Cell Death Dis. (2023) 14:115. doi: 10.1038/s41419-023-05596-4

  • CrossRef
  • Google Scholar

• 60

  LiuYDaM. Wilms tumor 1 associated protein promotes epithelial mesenchymal transition of gastric cancer cells by accelerating TGF-β and enhances chemoradiotherapy resistance. J Cancer Res Clin Oncol. (2023) 149:3977–88. doi: 10.1007/s00432-022-04320-7

  • CrossRef
  • Google Scholar

• 61

  WangHYangLLiuRHeHZhangMXuY. ADAR1 affects gastric cancer cell metastasis and reverses cisplatin resistance through AZIN1. Anticancer Drugs. (2023) 34:1132–45. doi: 10.1097/CAD.0000000000001516

  • CrossRef
  • Google Scholar

• 62

  Otaegi-UgartemendiaMMatheuACarrasco-GarciaE. Impact of cancer stem cells on therapy resistance in gastric cancer. Cancers (Basel). (2022) 14(6):1457. doi: 10.3390/cancers14061457

  • CrossRef
  • Google Scholar

• 63

  ZhangRLiuLWangFZhaoWLiuKYuHet al. AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA. Cell Death Dis. (2022) 13:1041. doi: 10.1038/s41419-022-05502-4

  • CrossRef
  • Google Scholar

• 64

  UkaiSHonmaRSakamotoNYamamotoYPhamQTHaradaKet al. Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell. Oncogene. (2020) 39:7265–78. doi: 10.1038/s41388-020-01492-9

  • CrossRef
  • Google Scholar

• 65

  LiKSunSLuYLiangWXuXZhangHet al. MT1M regulates gastric cancer progression and stemness by modulating the Hedgehog pathway protein GLI1. Biochem Biophys Res Commun. (2023) 670:63–72. doi: 10.1016/j.bbrc.2023.05.121

  • CrossRef
  • Google Scholar

• 66

  TanXYLiYTLiHHMaLXZengCMZhangTTet al. WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer. Oncogene. (2023) 42:3062–74. doi: 10.1038/s41388-023-02816-1

  • CrossRef
  • Google Scholar

• 67

  XuQGaoJZhaoRLiHCuiHYuanZet al. Akkermansia muciniphila-derived pentadecanoic acid enhances oxaliplatin sensitivity in gastric cancer by modulating glycolysis. Pharmacol Res. (2024) 206:107278. doi: 10.1016/j.phrs.2024.107278

  • CrossRef
  • Google Scholar

• 68

  HeDChenMChangLGuJLiuFGaoXet al. De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer. Cancer Lett. (2022) 549:215837. doi: 10.1016/j.canlet.2022.215837

  • CrossRef
  • Google Scholar

• 69

  WuZFangYWuJWangJLingYLiuTet al. Activation of glycolysis by MCM10 increases stemness and paclitaxel resistance in gastric cancer cells. Turk J Gastroenterol. (2023) 34:1107–15. doi: 10.5152/tjg.2023.23169

  • CrossRef
  • Google Scholar

• 70

  DaiYLiFJiaoYWangGZhanTXiaYet al. Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming. Cell Death Discovery. (2021) 7:140. doi: 10.1038/s41420-021-00517-w

  • CrossRef
  • Google Scholar

• 71

  ZhouYZhangQXuQLiaoBQiuX. circ_0006089 facilitates gastric cancer progression and oxaliplatin resistance via miR-217/NRP1. Pathol Res Pract. (2024) 263:155596. doi: 10.1016/j.prp.2024.155596

  • CrossRef
  • Google Scholar

• 72

  FeiYCaoDLiYWangZDongRZhuMet al. Circ_0008315 promotes tumorigenesis and cisplatin resistance and acts as a nanotherapeutic target in gastric cancer. J Nanobiotechnology. (2024) 22:519. doi: 10.1186/s12951-024-02760-6

  • CrossRef
  • Google Scholar

• 73

  XiangWZhangBLiH. LncRNA DLEU2 contributes to Taxol resistance of gastric cancer cells through regulating the miR-30c-5p-LDHA axis. J Chemother. (2024) 36:49–60. doi: 10.1080/1120009X.2023.2203606

  • CrossRef
  • Google Scholar

• 74

  JinWZhangHLiMLinS. Long Noncoding RNA Regulator of Reprogramming Regulates Cell Growth, Metastasis, and Cisplatin Resistance in Gastric Cancer via miR-519d-3p/HMGA2 Axis. Cancer Biother Radiopharm. (2023) 38:122–31. doi: 10.1089/cbr.2019.3525

  • CrossRef
  • Google Scholar

• 75

  ChenYLiuHZouJCaoGLiYXingCet al. Exosomal circ_0091741 promotes gastric cancer cell autophagy and chemoresistance via the miR-330-3p/TRIM14/Dvl2/Wnt/β-catenin axis. Hum Cell. (2023) 36:258–75. doi: 10.1007/s13577-022-00790-6

  • CrossRef
  • Google Scholar

• 76

  ZengZWChenDChenLHeBLiY. A comprehensive overview of Artemisinin and its derivatives as anticancer agents. Eur J Med Chem. (2023) 247:115000. doi: 10.1016/j.ejmech.2022.115000

  • CrossRef
  • Google Scholar

• 77

  WangHDingQZhouHHuangCLiuGZhaoXet al. Dihydroartemisinin inhibited vasculogenic mimicry in gastric cancer through the FGF2/FGFR1 signaling pathway. Phytomedicine. (2024) 134:155962. doi: 10.1016/j.phymed.2024.155962

  • CrossRef
  • Google Scholar

• 78

  LuoQZhangSZhangDFengRLiNChenWet al. Effects and mechanisms of anlotinib and dihydroartemisinin combination therapy in ameliorating Malignant biological behavior of gastric cancer cells. Curr Pharm Biotechnol. (2021) 22:523–33. doi: 10.2174/1389201021666200623132803

  • CrossRef
  • Google Scholar

• 79

  LiNZhangSLuoQYuanFFengRChenXet al. The effect of dihydroartemisinin on the Malignancy and epithelial-mesenchymal transition of gastric cancer cells. Curr Pharm Biotechnol. (2019) 20:719–26. doi: 10.2174/1389201020666190611124644

  • CrossRef
  • Google Scholar

• 80

  ZhangPLuoHSLiMTanSY. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2. Onco Targets Ther. (2015) 8:845–54. doi: 10.2147/OTT.S81041

  • CrossRef
  • Google Scholar

• 81

  SuTLiFGuanJLiuLHuangPWangYet al. Artemisinin and its derivatives prevent Helicobacter pylori-induced gastric carcinogenesis via inhibition of NF-κB signaling. Phytomedicine. (2019) 63:152968. doi: 10.1016/j.phymed.2019.152968

  • CrossRef
  • Google Scholar

• 82

  YangLHuZZhuJLiangQZhouHLiJet al. Systematic Elucidation of the Mechanism of Quercetin against Gastric Cancer via Network Pharmacology Approach. BioMed Res Int. (2020) 2020:3860213. doi: 10.1155/2020/3860213

  • CrossRef
  • Google Scholar

• 83

  ShenXSiYWangZWangJGuoYZhangX. Quercetin inhibits the growth of human gastric cancer stem cells by inducing mitochondrial-dependent apoptosis through the inhibition of PI3K/Akt signaling. Int J Mol Med. (2016) 38:619–26. doi: 10.3892/ijmm.2016.2625

  • CrossRef
  • Google Scholar

• 84

  DingLDangSSunMZhouDSunYLiEet al. Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes. Free Radic Biol Med. (2024) 213:150–63. doi: 10.1016/j.freeradbiomed.2024.01.002

  • CrossRef
  • Google Scholar

• 85

  RongYLiuSHTangMZYangXJ. Quercetin inhibits the proliferative effect of gastric cancer cells by activating the pyroptosis pathway. Asian J Surg. (2023) 46:5286–8. doi: 10.1016/j.asjsur.2023.07.051

  • CrossRef
  • Google Scholar

• 86

  GuanZChenJLiXDongN. Tanshinone IIA induces ferroptosis in gastric cancer cells through p53-mediated SLC7A11 down-regulation. Biosci Rep. (2020) 40(8):BSR20201807. doi: 10.1042/BSR20201807

  • CrossRef
  • Google Scholar

• 87

  HouJHeJJinXHuTZhangY. Study on optimisation of extraction process of tanshinone IIA and its mechanism of induction of gastric cancer SGC7901 cell apoptosis. Afr J Tradit Complement Altern Med. (2013) 10:456–8. doi: 10.4314/ajtcam.v10i6.10

  • CrossRef
  • Google Scholar

• 88

  XiaMWuYZhuHDuanW. Tanshinone I induces ferroptosis in gastric cancer cells via the KDM4D/p53 pathway. Hum Exp Toxicol. (2023) 42:9603271231216963. doi: 10.1177/09603271231216963

  • CrossRef
  • Google Scholar

• 89

  LiangDTangSLiuLZhaoMMaXZhaoYet al. Tanshinone I attenuates gastric precancerous lesions by inhibiting epithelial mesenchymal transition through the p38/STAT3 pathway. Int Immunopharmacol. (2023) 124:110902. doi: 10.1016/j.intimp.2023.110902

  • CrossRef
  • Google Scholar

• 90

  YuJRLiuYYGaoYYQianLHQiuJLWangPPet al. Diterpenoid tanshinones inhibit gastric cancer angiogenesis through the PI3K/Akt/mTOR signaling pathway. J Ethnopharmacol. (2024) 324:117791. doi: 10.1016/j.jep.2024.117791

  • CrossRef
  • Google Scholar

• 91

  WangNYangJLuJQiaoQWuTDuXet al. A polysaccharide from Salvia miltiorrhiza Bunge improves immune function in gastric cancer rats. Carbohydr Polym. (2014) 111:47–55. doi: 10.1016/j.carbpol.2014.04.061

  • CrossRef
  • Google Scholar

• 92

  XiaDLiWTangCJiangJ. Astragaloside IV, as a potential anticancer agent. Front Pharmacol. (2023) 14:1065505. doi: 10.3389/fphar.2023.1065505

  • CrossRef
  • Google Scholar

• 93

  ZhuJWenK. Astragaloside IV inhibits TGF-β1-induced epithelial-mesenchymal transition through inhibition of the PI3K/Akt/NF-κB pathway in gastric cancer cells. Phytother Res. (2018) 32:1289–96. doi: 10.1002/ptr.v32.7

  • CrossRef
  • Google Scholar

• 94

  WangZFMaDGZhuZMuYPYangYYFengLet al. Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts. World J Gastroenterol. (2017) 23:8512–25. doi: 10.3748/wjg.v23.i48.8512

  • CrossRef
  • Google Scholar

• 95

  ZhangCCaiTZengXCaiDChenYHuangXet al. Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway. Phytother Res. (2018) 32:1364–72. doi: 10.1002/ptr.v32.7

  • CrossRef
  • Google Scholar

• 96

  AuyeungKKWooPKLawPCKoJK. Astragalus saponins modulate cell invasiveness and angiogenesis in human gastric adenocarcinoma cells. J Ethnopharmacol. (2012) 141:635–41. doi: 10.1016/j.jep.2011.08.010

  • CrossRef
  • Google Scholar

• 97

  ZhangYZhangJQZhangTXueHZuoWBLiYNet al. Calycosin induces gastric cancer cell apoptosis via the ROS-mediated MAPK/STAT3/NF-κB pathway. Onco Targets Ther. (2021) 14:2505–17. doi: 10.2147/OTT.S292388

  • CrossRef
  • Google Scholar

• 98

  LiDZhaoLLiYKangXZhangS. Gastro-protective effects of calycosin against precancerous lesions of gastric carcinoma in rats. Drug Des Devel Ther. (2020) 14:2207–19. doi: 10.2147/DDDT.S247958

  • CrossRef
  • Google Scholar

• 99

  XiGDongQYangBJiaoDKhanS. Curcumin's dose-dependent attenuation of gastric cancer cell progression via the PI3K pathway blockade. Dose Response. (2023) 21:15593258231203585. doi: 10.1177/15593258231203585

  • CrossRef
  • Google Scholar

• 100

  FuHWangCYangDWeiZXuJHuZet al. Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling. J Cell Physiol. (2018) 233:4634–42. doi: 10.1002/jcp.v233.6

  • CrossRef
  • Google Scholar

• 101

  BaderAGKangSZhaoLVogtPK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. (2005) 5:921–9. doi: 10.1038/nrc1753

  • CrossRef
  • Google Scholar

• 102

  FrumanDAChiuHHopkinsBDBagrodiaSCantleyLCAbrahamRT. The PI3K pathway in human disease. Cell. (2017) 170:605–35. doi: 10.1016/j.cell.2017.07.029

  • CrossRef
  • Google Scholar

• 103

  VasudevanKMBarbieDADaviesMARabinovskyRMcNearCJKimJJet al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. (2009) 16:21–32. doi: 10.1016/j.ccr.2009.04.012

  • CrossRef
  • Google Scholar

• 104

  RascioFSpadaccinoFRocchettiMTCastellanoGStalloneGNettiGSet al. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review. Cancers (Basel). (2021) 13(16):3949. doi: 10.3390/cancers13163949

  • CrossRef
  • Google Scholar

• 105

  LiuBWangCChenPChengBChengY. RACKI induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression. Onco Targets Ther. (2018) 11:211–20. doi: 10.2147/OTT.S152818

  • CrossRef
  • Google Scholar

• 106

  LiuRChenYLiuGLiCSongYCaoZet al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. (2020) 11:797. doi: 10.1038/s41419-020-02998-6

  • CrossRef
  • Google Scholar

• 107

  GuJHuangWWangXZhangJTaoTZhengYet al. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer. (2022) 21:112. doi: 10.1186/s12943-022-01587-9

  • CrossRef
  • Google Scholar

• 108

  DongSLiangSChengZZhangXLuoLLiLet al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J Exp Clin Cancer Res. (2022) 41:15. doi: 10.1186/s13046-021-02229-6

  • CrossRef
  • Google Scholar

• 109

  GuoLShiHZhuL. Siteng fang reverses multidrug resistance in gastric cancer: A network pharmacology and molecular docking study. Front Oncol. (2021) 11:671382. doi: 10.3389/fonc.2021.671382

  • CrossRef
  • Google Scholar

• 110

  ZhaoGXueS. Mechanism of quercetin as a multidrug-resistant reversing compound in oxaliplatin-resistant gastric-cancer cell lines. Altern Ther Health Med. (2023) 29:54–9.

  • Google Scholar

• 111

  ZhanDNiTWangHLvMSunagawaMLiuY. Celastrol inhibits the proliferation and decreases drug resistance of cisplatin- resistant gastric cancer SGC7901/DDP cells. Anticancer Agents Med Chem. (2022) 22:270–9. doi: 10.2174/1871520621666210528144006

  • CrossRef
  • Google Scholar

• 112

  ZhangSFengRYuanFLuoQChenXLiNet al. The therapeutic effects of dihydroartemisinin on cisplatin-resistant gastric cancer cells. Curr Pharm Biotechnol. (2022) 23:276–86. doi: 10.2174/1389201022666210217114825

  • CrossRef
  • Google Scholar

• 113

  WangXHeRGengLYuanJFanH. Ginsenoside rg3 alleviates cisplatin resistance of gastric cancer cells through inhibiting SOX2 and the PI3K/akt/mTOR signaling axis by up-regulating miR-429. Front Genet. (2022) 13:823182. doi: 10.3389/fgene.2022.823182

  • CrossRef
  • Google Scholar

• 114

  FuLHanBKMengFFWangJWWangTYLiHJet al. Jaridon 6, a new diterpene from Rabdosia rubescens (Hemsl.) Hara, can display anti-gastric cancer resistance by inhibiting SIRT1 and inducing autophagy. Phytother Res. (2021) 35:5720–33. doi: 10.1002/ptr.v35.10

  • CrossRef
  • Google Scholar

• 115

  ChenFZhuangMZhongCPengJWangXLiJet al. Baicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1α signaling pathway. Oncol Rep. (2015) 33:457–63. doi: 10.3892/or.2014.3550

  • CrossRef
  • Google Scholar

• 116

  KouYTongBWuWLiaoXZhaoM. Berberine improves chemo-sensitivity to cisplatin by enhancing cell apoptosis and repressing PI3K/AKT/mTOR signaling pathway in gastric cancer. Front Pharmacol. (2020) 11:616251. doi: 10.3389/fphar.2020.616251

  • CrossRef
  • Google Scholar

• 117

  XuRWuJZhangXZouXLiCWangHet al. Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracile to inhibits gastric cancer progress via PD-1/PD- L1-dependent T cell immunization. Pharmacol Res. (2020) 152:104623. doi: 10.1016/j.phrs.2019.104623

  • CrossRef
  • Google Scholar

• 118

  TangHHuangWYangQLinYChenYShuP. Jianpi Yangwei decoction promotes apoptosis and suppresses proliferation of 5-fluorouracil resistant gastric cancer cells in vitro and in vivo. BMC Complement Med Ther. (2020) 20:337. doi: 10.1186/s12906-020-03135-8

  • CrossRef
  • Google Scholar

• 119

  BaldwinAS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. (2001) 107:241–6. doi: 10.1172/JCI11991

  • CrossRef
  • Google Scholar

• 120

  GiridharanSSrinivasanM. Mechanisms of NF-κB p65 and strategies for therapeutic manipulation. J Inflammation Res. (2018) 11:407–19. doi: 10.2147/JIR.S140188

  • CrossRef
  • Google Scholar

• 121

  BaeuerlePAHenkelT. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. (1994) 12:141–79. doi: 10.1146/annurev.iy.12.040194.001041

  • CrossRef
  • Google Scholar

• 122

  YuHLinLZhangZZhangHHuH. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. (2020) 5:209. doi: 10.1038/s41392-020-00312-6

  • CrossRef
  • Google Scholar

• 123

  HoeselBSchmidJA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. (2013) 12:86. doi: 10.1186/1476-4598-12-86

  • CrossRef
  • Google Scholar

• 124

  SongWLiangCSunYMoriiSYomogidaSIsajiTet al. Expression of GnT-III decreases chemoresistance via negatively regulating P-glycoprotein expression: Involvement of the TNFR2-NF-κB signaling pathway. J Biol Chem. (2023) 299:103051. doi: 10.1016/j.jbc.2023.103051

  • CrossRef
  • Google Scholar

• 125

  LiYXuCHanHPascual-SabaterSFillatCGoelA. Aronia berry extract modulates MYD88/NF-kB/P-glycoprotein axis to overcome gemcitabine resistance in pancreatic cancer. Pharm (Basel). (2024) 17(7):911. doi: 10.3390/ph17070911

  • CrossRef
  • Google Scholar

• 126

  LinHNiRLiDZhaoMLiYLiKet al. LncRNA MIR155HG overexpression promotes proliferation, migration, and chemoresistance in gastric cancer cells. Int J Med Sci. (2023) 20:933–42. doi: 10.7150/ijms.82216

  • CrossRef
  • Google Scholar

• 127

  YanMChenXYeQLiHZhangLWangY. IL-33-dependent NF-κB activation inhibits apoptosis and drives chemoresistance in acute myeloid leukemia. Cytokine. (2024) 180:156672. doi: 10.1016/j.cyto.2024.156672

  • CrossRef
  • Google Scholar

• 128

  ZhangXZhengSHuCLiGLinHXiaRet al. Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair. Oncogene. (2022) 41:2372–89. doi: 10.1038/s41388-022-02253-6

  • CrossRef
  • Google Scholar

• 129

  ZhaiJShenJXieGWuJHeMGaoLet al. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. (2019) 454:37–43. doi: 10.1016/j.canlet.2019.04.002

  • CrossRef
  • Google Scholar

• 130

  FuZHLiuSQQinMBHuangJAXuCYWuWHet al. NIK− and IKKβ−binding protein contributes to gastric cancer chemoresistance by promoting epithelial−mesenchymal transition through the NF−κB signaling pathway. Oncol Rep. (2018) 39:2721–30. doi: 10.3892/or.2018.6348

  • CrossRef
  • Google Scholar

• 131

  DunSGaoL. Tanshinone I attenuates proliferation and chemoresistance of cervical cancer in a KRAS-dependent manner. J Biochem Mol Toxicol. (2019) 33:e22267. doi: 10.1002/jbt.2019.33.issue-4

  • CrossRef
  • Google Scholar

• 132

  WangGLiYGuoZHeQLiuZDengB. Tanshinone I stimulates pyroptosis of cisplatin-resistant gastric cancer cells by activating the NF-κB/caspase-3(8)/GSDME signaling pathway. DNA Cell Biol. (2024) 43:185–96. doi: 10.1089/dna.2023.0293

  • CrossRef
  • Google Scholar

• 133

  SohmaIFujiwaraYSugitaYYoshiokaAShirakawaMMoonJHet al. Parthenolide, an NF-κB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer. Cancer Genomics Proteomics. (2011) 8:39–47.

  • Google Scholar

• 134

  MoradiMTAltememyDAsadi-SamaniMKhosravianPSoltaniMHashemiLet al. The effect of celastrol in combination with 5-fluorouracil on proliferation and apoptosis of gastric cancer cell lines. Oncol Res. (2024) 32:1231–7. doi: 10.32604/or.2024.047187

  • CrossRef
  • Google Scholar

• 135

  HuangXQianJLiLZhangXWeiGLvJet al. Curcumol improves cisplatin sensitivity of human gastric cancer cells through inhibiting PI3K/AKT pathway. Drug Dev Res. (2020) 81:1019–25. doi: 10.1002/ddr.21719

  • CrossRef
  • Google Scholar

• 136

  HuYXuRMaJYanZMaJ. Curcumol enhances cisplatin sensitivity of gastric cancer: involvement of microRNA-7 and the nuclear factor-kappa B/snail family transcriptional repressor 1 axis. Bioengineered. (2022) 13:11668–83. doi: 10.1080/21655979.2022.2070975

  • CrossRef
  • Google Scholar

• 137

  ZhaoQWangJZouMJHuRZhaoLQiangLet al. Wogonin potentiates the antitumor effects of low dose 5-fluorouracil against gastric cancer through induction of apoptosis by down-regulation of NF-kappaB and regulation of its metabolism. Toxicol Lett. (2010) 197:201–10. doi: 10.1016/j.toxlet.2010.05.019

  • CrossRef
  • Google Scholar

• 138

  YuLLWuJGDaiNYuHGSiJM. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol Rep. (2011) 26:1197–203. doi: 10.3892/or.2011.1410

  • CrossRef
  • Google Scholar

• 139

  WuHLiWWangTShuYLiuP. Paeoniflorin suppress NF-kappaB activation through modulation of I kappaB alpha and enhances 5-fluorouracil-induced apoptosis in human gastric carcinoma cells. BioMed Pharmacother. (2008) 62:659–66. doi: 10.1016/j.biopha.2008.08.002

  • CrossRef
  • Google Scholar

• 140

  SuriyaUMahalapbutrPRungrotmongkolT. Integration of In Silico Strategies for Drug Repositioning towards P38α Mitogen-Activated Protein Kinase (MAPK) at the Allosteric Site. Pharmaceutics. (2022) 14(7):1461. doi: 10.3390/pharmaceutics14071461

  • CrossRef
  • Google Scholar

• 141

  IroegbuJDIjomoneOKFemi-AkinlosotuOMIjomoneOM. ERK/MAPK signalling in the developing brain: Perturbations and consequences. Neurosci Biobehav Rev. (2021) 131:792–805. doi: 10.1016/j.neubiorev.2021.10.009

  • CrossRef
  • Google Scholar

• 142

  BaharMEKimHJKimDR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. (2023) 8:455. doi: 10.1038/s41392-023-01705-z

  • CrossRef
  • Google Scholar

• 143

  ZekeAMishevaMReményiABogoyevitchMA. JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev. (2016) 80:793–835. doi: 10.1128/MMBR.00043-14

  • CrossRef
  • Google Scholar

• 144

  PuaLJWMaiCWChungFFKhooASLeongCOLimWMet al. Functional roles of JNK and p38 MAPK signaling in nasopharyngeal carcinoma. Int J Mol Sci. (2022) 23(3):1108. doi: 10.3390/ijms23031108

  • CrossRef
  • Google Scholar

• 145

  PanneerpandianPRaoDBGanesanK. Calcium channel blockers lercanidipine and amlodipine inhibit YY1/ERK/TGF-β mediated transcription and sensitize the gastric cancer cells to doxorubicin. Toxicol In Vitro. (2021) 74:105152. doi: 10.1016/j.tiv.2021.105152

  • CrossRef
  • Google Scholar

• 146

  ChenBJinFLuPLuXLWangPPLiuYPet al. Effect of mitogen-activated protein kinase signal transduction pathway on multidrug resistance induced by vincristine in gastric cancer cell line MGC803. World J Gastroenterol. (2004) 10:795–9. doi: 10.3748/wjg.v10.i6.795

  • CrossRef
  • Google Scholar

• 147

  SuiXKongNYeLHanWZhouJZhangQet al. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. (2014) 344:174–9. doi: 10.1016/j.canlet.2013.11.019

  • CrossRef
  • Google Scholar

• 148

  LowHBWongZLWuBKongLRPngCWChoYLet al. DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death. Nat Commun. (2021) 12:2284. doi: 10.1038/s41467-021-22638-7

  • CrossRef
  • Google Scholar

• 149

  ChungLYTangSJSunGHChouTYYehTSYuSLet al. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin Cancer Res. (2012) 18:4037–47. doi: 10.1158/1078-0432.CCR-11-3348

  • CrossRef
  • Google Scholar

• 150

  LimamiYPinonALegerDYPinaultEDelageCBeneytoutJLet al. The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells. Biochimie. (2012) 94:1754–63. doi: 10.1016/j.biochi.2012.04.006

  • CrossRef
  • Google Scholar

• 151

  ZhouPYaoWLiuLYanQChenXWeiXet al. SPG21, a potential oncogene targeted by miR-128-3p, amplifies HBx-induced carcinogenesis and chemoresistance via activation of TRPM7-mediated JNK pathway in hepatocellular carcinoma. Cell Oncol (Dordr). (2024) 47:1757–78. doi: 10.1007/s13402-024-00955-5

  • CrossRef
  • Google Scholar

• 152

  PengZGuanQLuoJDengWLiuJYanRet al. Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer. BMC Cancer. (2020) 20:582. doi: 10.1186/s12885-020-07067-x

  • CrossRef
  • Google Scholar

• 153

  RenDLGhoorunRAWuXHChenHLZhouQWuXB. Oridonin induces apoptosis in HGC-27 cells by activating the JNK signaling pathway. Oncol Lett. (2020) 19:255–60. 10.3892/ol.2019.11104

  • Google Scholar

• 154

  HongZPWangLGWangHJYeWFWangXZ. Wogonin exacerbates the cytotoxic effect of oxaliplatin by inducing nitrosative stress and autophagy in human gastric cancer cells. Phytomedicine. (2018) 39:168–75. doi: 10.1016/j.phymed.2017.12.019

  • CrossRef
  • Google Scholar

• 155

  YangLLiuYNGuYGuoQ. Deltonin enhances gastric carcinoma cell apoptosis and chemosensitivity to cisplatin via inhibiting PI3K/AKT/mTOR and MAPK signaling. World J Gastrointest Oncol. (2023) 15:1739–55. doi: 10.4251/wjgo.v15.i10.1739

  • CrossRef
  • Google Scholar

• 156

  ShimJHGimHLeeSKimBJ. Inductions of caspase-, MAPK- and ROS-dependent apoptosis and chemotherapeutic effects caused by an ethanol extract of scutellaria barbata D. Don Hum Gastric Adenocarcinom Cells J Pharmacopuncture. (2016) 19:129–36. doi: 10.3831/KPI.2016.19.014

  • CrossRef
  • Google Scholar

• 157

  LiuSQXuCYQinMBTanLZhugeCFMaoYBet al. Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells. Oncol Rep. (2015) 33:2871–82. doi: 10.3892/or.2015.3923

  • CrossRef
  • Google Scholar

• 158

  LiuYTavanaOGuW. p53 modifications: exquisite decorations of the powerful guardian. J Mol Cell Biol. (2019) 11:564–77. doi: 10.1093/jmcb/mjz060

  • CrossRef
  • Google Scholar

• 159

  WangXSimpsonERBrownKA. p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis. Cancer Res. (2015) 75:5001–7. doi: 10.1158/0008-5472.CAN-15-0563

  • CrossRef
  • Google Scholar

• 160

  JoergerACFershtAR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. (2016) 85:375–404. doi: 10.1146/annurev-biochem-060815-014710

  • CrossRef
  • Google Scholar

• 161

  DiYJingXHuKWenXYeLZhangXet al. The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity. Drug Resist Updat. (2023) 66:100909. doi: 10.1016/j.drup.2022.100909

  • CrossRef
  • Google Scholar

• 162

  MengJQianWYangZGongLXuDHuangHet al. p53/E2F7 axis promotes temozolomide chemoresistance in glioblastoma multiforme. BMC Cancer. (2024) 24:317. doi: 10.1186/s12885-024-12017-y

  • CrossRef
  • Google Scholar

• 163

  YangLZhouYLiYZhouJWuYCuiYet al. Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Lett. (2015) 357:520–6. doi: 10.1016/j.canlet.2014.12.003

  • CrossRef
  • Google Scholar

• 164

  XuZChenLXiaoZZhuYJiangHJinYet al. Potentiation of the anticancer effect of doxorubicinin drug-resistant gastric cancer cells by tanshinone IIA. Phytomedicine. (2018) 51:58–67. doi: 10.1016/j.phymed.2018.05.012

  • CrossRef
  • Google Scholar

• 165

  BiELiuDLiYMaoXWangAWangJ. Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function. Braz J Med Biol Res. (2018) 51:e7599. doi: 10.1590/1414-431x20187599

  • CrossRef
  • Google Scholar

• 166

  WeiFJiangXGaoHYGaoSH. Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo. Int J Oncol. (2017) 51:1383–94. doi: 10.3892/ijo.2017.4134

  • CrossRef
  • Google Scholar

• 167

  ShaoLZhuLSuRYangCGaoXXuYet al. Baicalin enhances the chemotherapy sensitivity of oxaliplatin-resistant gastric cancer cells by activating p53-mediated ferroptosis. Sci Rep. (2024) 14:10745. doi: 10.1038/s41598-024-60920-y

  • CrossRef
  • Google Scholar

• 168

  Al-BahlaniSBurneyIAAl-DhahliBAl-KharusiSAl-KharousiFAl-KalbaniAet al. Boswellic acid sensitizes gastric cancer cells to Cisplatin-induced apoptosis via p53-mediated pathway. BMC Pharmacol Toxicol. (2020) 21:64. doi: 10.1186/s40360-020-00442-1

  • CrossRef
  • Google Scholar

• 169

  KimBRJeongYAKimDYKimJLJeongSNaYJet al. Genipin increases oxaliplatin-induced cell death through autophagy in gastric cancer. J Cancer. (2020) 11:460–7. doi: 10.7150/jca.34773

  • CrossRef
  • Google Scholar

• 170

  LeeSLeeSKJungJ. Potentiating activities of chrysin in the therapeutic efficacy of 5-fluorouracil in gastric cancer cells. Oncol Lett. (2021) 21:24. doi: 10.3892/ol.2020.12285

  • CrossRef
  • Google Scholar

• 171

  SiveenKSSikkaSSuranaRDaiXZhangJKumarAPet al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. (2014) 1845:136–54. doi: 10.1016/j.bbcan.2013.12.005

  • CrossRef
  • Google Scholar

• 172

  GarbersCAparicio-SiegmundSRose-JohnS. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol. (2015) 34:75–82. doi: 10.1016/j.coi.2015.02.008

  • CrossRef
  • Google Scholar

• 173

  VerhoevenYTilborghsSJacobsJDe WaeleJQuatannensDDebenCet al. The potential and controversy of targeting STAT family members in cancer. Semin Cancer Biol. (2020) 60:41–56. doi: 10.1016/j.semcancer.2019.10.002

  • CrossRef
  • Google Scholar

• 174

  MaJHQinLLiX. Role of STAT3 signaling pathway in breast cancer. Cell Commun Signal. (2020) 18:33. doi: 10.1186/s12964-020-0527-z

  • CrossRef
  • Google Scholar

• 175

  HashemiVMasjediAHazhir-KarzarBTanomandAShotorbaniSSHojjat-FarsangiMet al. The role of DEAD-box RNA helicase p68 (DDX5) in the development and treatment of breast cancer. J Cell Physiol. (2019) 234:5478–87. doi: 10.1002/jcp.v234.5

  • CrossRef
  • Google Scholar

• 176

  YouLWangZLiHShouJJingZXieJet al. The role of STAT3 in autophagy. Autophagy. (2015) 11:729–39. doi: 10.1080/15548627.2015.1017192

  • CrossRef
  • Google Scholar

• 177

  ShihPCMeiKC. Role of STAT3 signaling transduction pathways in cancer stem cell-associated chemoresistance. Drug Discovery Today. (2021) 26:1450–8. doi: 10.1016/j.drudis.2020.11.032

  • CrossRef
  • Google Scholar

• 178

  ShiCYangJHuLLiaoBQiaoLShenWet al. Glycochenodeoxycholic acid induces stemness and chemoresistance via the STAT3 signaling pathway in hepatocellular carcinoma cells. Aging (Albany NY). (2020) 12:15546–55. doi: 10.18632/aging.103751

  • CrossRef
  • Google Scholar

• 179

  SadrkhanlooMPaskehMDAHashemiMRaesiRMotahharyMSaghariSet al. STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions. BioMed Pharmacother. (2023) 158:114168. doi: 10.1016/j.biopha.2022.114168

  • CrossRef
  • Google Scholar

• 180

  WangTFahrmannJFLeeHLiYJTripathiSCYueCet al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. (2018) 27:136–50.e5. doi: 10.1016/j.cmet.2017.11.001

  • CrossRef
  • Google Scholar

• 181

  SuPYuTZhangYHuangHChenMCaoCet al. Upregulation of MELK promotes chemoresistance and induces macrophage M2 polarization via CSF-1/JAK2/STAT3 pathway in gastric cancer. Cancer Cell Int. (2024) 24:287. doi: 10.1186/s12935-024-03453-8

  • CrossRef
  • Google Scholar

• 182

  WuWCaoYChengLWangLYuQPengHet al. Cryptotanshinone from Salvia miltiorrhiza inhibits the growth of tumors and enhances the efficacy of chemotherapy in a gastric cancer mouse model. Natural Product Commun. (2022) 17:1934578X221130874. doi: 10.1177/1934578X221130874

  • CrossRef
  • Google Scholar

• 183

  CaoYWangLChengLChuJYuQPengHet al. Cryptotanshinone inhibits the proliferation of 5-fluorouracil-resistant gastric cancer SGC-7901/5-FU cells via the JAK2/STAT3 pathway. Pharm Chem J. (2024) 58:187–96. doi: 10.1007/s11094-024-03133-x

  • CrossRef
  • Google Scholar

• 184

  WangJZhangGDaiCGaoXWuJShenLet al. Cryptotanshinone potentiates the antitumor effects of doxorubicin on gastric cancer cells via inhibition of STAT3 activity. J Int Med Res. (2017) 45:220–30. doi: 10.1177/0300060516685513

  • CrossRef
  • Google Scholar

• 185

  HeLChenHQiQWuNWangYChenMet al. Schisandrin B suppresses gastric cancer cell growth and enhances the efficacy of chemotherapy drug 5-FU in vitro and in vivo. Eur J Pharmacol. (2022) 920:174823. doi: 10.1016/j.ejphar.2022.174823

  • CrossRef
  • Google Scholar

• 186

  PandeyAVishnoiKMahataSTripathiSCMisraSPMisraVet al. Berberine and curcumin target survivin and STAT3 in gastric cancer cells and synergize actions of standard chemotherapeutic 5-fluorouracil. Nutr Cancer. (2015) 67:1293–304. doi: 10.1080/01635581.2015.1085581

  • CrossRef
  • Google Scholar

• 187

  LiHLuHLvMWangQSunY. Parthenolide facilitates apoptosis and reverses drug-resistance of human gastric carcinoma cells by inhibiting the STAT3 signaling pathway. Oncol Lett. (2018) 15:3572–9. doi: 10.3892/ol.2018.7739

  • CrossRef
  • Google Scholar

• 188

  FengXXueFHeGNiQHuangS. Banxia xiexin decoction affects drug sensitivity in gastric cancer cells by regulating MGMT expression via IL−6/JAK/STAT3−mediated PD−L1 activity. Int J Mol Med. (2021) 48(2):165. doi: 10.3892/ijmm.2021.4998

  • CrossRef
  • Google Scholar

• 189

  BellamNPascheB. Tgf-beta signaling alterations and colon cancer. Cancer Treat Res. (2010) 155:85–103. doi: 10.1007/978-1-4419-6033-7_5

  • CrossRef
  • Google Scholar

• 190

  ZhangMZhangYYChenYWangJWangQLuH. TGF-β Signaling and resistance to cancer therapy. Front Cell Dev Biol. (2021) 9:786728. doi: 10.3389/fcell.2021.786728

  • CrossRef
  • Google Scholar

• 191

  LeeCHTsaiHYChenCLChenJLLuCCFangYPet al. Isoliquiritigenin inhibits gastric cancer stemness, modulates tumor microenvironment, and suppresses tumor growth through glucose-regulated protein 78 downregulation. Biomedicines. (2022) 10(6):1350. doi: 10.3390/biomedicines10061350

  • CrossRef
  • Google Scholar

• 192

  ZhangYHuangPLiuXXiangYZhangTWuYet al. Polyphyllin I inhibits growth and invasion of cisplatin-resistant gastric cancer cells by partially inhibiting CIP2A/PP2A/Akt signaling axis. J Pharmacol Sci. (2018) 137:305–12. doi: 10.1016/j.jphs.2018.07.008

  • CrossRef
  • Google Scholar

• 193

  ZhouYChenYShiYWuLTanYLiTet al. FAM117B promotes gastric cancer growth and drug resistance by targeting the KEAP1/NRF2 signaling pathway. J Clin Invest. (2023) 133(3):e158705. doi: 10.1172/JCI158705

  • CrossRef
  • Google Scholar

• 194

  FarkhondehTPourbagher-ShahriAMAzimi-NezhadMForouzanfarFBrockmuellerAAshrafizadehMet al. Roles of nrf2 in gastric cancer: targeting for therapeutic strategies. Molecules. (2021) 26(11):3157. doi: 10.3390/molecules26113157

  • CrossRef
  • Google Scholar

• 195

  LiPHuJShiBTieJ. Baicalein enhanced cisplatin sensitivity of gastric cancer cells by inducing cell apoptosis and autophagy via Akt/mTOR and Nrf2/Keap 1 pathway. Biochem Biophys Res Commun. (2020) 531:320–7. doi: 10.1016/j.bbrc.2020.07.045

  • CrossRef
  • Google Scholar

• 196

  HuangWWenFGuPLiuJXiaYLiYet al. The inhibitory effect and mechanism of Yi-qi-hua-yu-jie-du decoction on the drug resistance of gastric cancer stem cells based on ABC transporters. Chin Med. (2022) 17:93. doi: 10.1186/s13020-022-00647-y

  • CrossRef
  • Google Scholar

• 197

  HuangWWenFYangPLiYLiQShuP. Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3β/NRF2/GPX4 axis. Phytomedicine. (2024) 123:155220. doi: 10.1016/j.phymed.2023.155220

  • CrossRef
  • Google Scholar

• 198

  CruciatCMNiehrsC. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. (2013) 5:a015081. doi: 10.1101/cshperspect.a015081

  • CrossRef
  • Google Scholar

• 199

  LiuJXiaoQXiaoJNiuCLiYZhangXet al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. (2022) 7:3. doi: 10.1038/s41392-021-00762-6

  • CrossRef
  • Google Scholar

• 200

  CaiWChenGLuoQLiuJGuoXZhangTet al. PMP22 regulates self-renewal and chemoresistance of gastric cancer cells. Mol Cancer Ther. (2017) 16:1187–98. doi: 10.1158/1535-7163.MCT-16-0750

  • CrossRef
  • Google Scholar

• 201

  HosseiniFSNoroozi KarimabadMHajizadehMRKhoshdelAKhanamani-Falahati-PourSMirzaeiMRet al. Evaluating of induction of apoptosis by cornus mass L. Extract in the gastric carcinoma cell line (AGS). Asian Pac J Cancer Prev. (2019) 20:123–30. doi: 10.31557/APJCP.2019.20.1.123

  • CrossRef
  • Google Scholar

• 202

  ZhouHHuXLiNLiGSunXGeFet al. Loganetin and 5-fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down-regulation of the Wnt/β-catenin pathway. J Cell Mol Med. (2020) 24:13715–26. doi: 10.1111/jcmm.v24.23

  • CrossRef
  • Google Scholar

• 203

  HouGYuanXLiYHouGLiuX. Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/β-catenin signal pathway. Invest New Drugs. (2020) 38:329–39. doi: 10.1007/s10637-019-00781-9

  • CrossRef
  • Google Scholar

• 204

  MengZQZhangRWuXWJinTFZhangMH. Ginsenoside rg3 regulates cisplatin resistance in gastric cancer by wnt/β-catenin signaling pathway. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. (2022) 44:366–76. 10.3881/j.issn.1000-503X.14775

  • Google Scholar