Targetable pathways for drug repurposing in gastric cancer

Abstract

Gastric cancer (GC) is both the fifth most common cancer worldwide and the fifth in mortality. Owing to a lack of symptoms in the early stages and unspecific clinical presentation in the later stages, GC is usually diagnosed at advanced stages. This means that only approximately 60% of patients are eligible for curative treatment, and overall, GC patients have a 5-year survival rate of only 28.3%, underscoring the importance of developing new treatment strategies. Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time. A variety of targetable pathways are involved in GC progression, including the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, p53, Janus kinase 2/signal transducer and activator of transcription 3, hypoxia-inducible factor-1α, wingless-type mouse mammary tumor virus integration site family/beta-catenin (Wnt/β-catenin), nuclear factor kappa B, and Hippo pathways. Therefore, the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC. In this review, we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.

Key Words: Gastric cancer; Drug repurposing; Signaling pathways; Correa’s cascade; Cancer therapy

Core Tip: Gastric cancer patients have a dismal prognosis when it is detected in advanced stages, so the search for new treatments is imperative to improve survival rates. In this review, we explored the potential of repurposed drugs for targeting pathways related to the development and progression of gastric cancer, as their lower costs and faster development make them promising candidates in the search for new therapies to treat this disease.

INTRODUCTION

Gastric cancer (GC) is both the fifth most common cancer worldwide and the fifth in mortality, representing almost 1000000 new cases and 650000 deaths in 2022[1]. The incidence of GC differs by region. The highest incidence rates are in East Asia, Central and Eastern Europe, and South America, and a lower incidence occurs in Western Europe and North America[2,3].

The histological classification of GC distinguishes between diffuse- and intestinal-type GC, with the latter type being more common and usually associated with Helicobacter pylori (H. pylori) infection[4]. Intestinal-type GC accounts for approximately 54% of GC cases, diffuse-type GC represents approximately 32%, and approximately 15% of cases present an indeterminate histology. Diffuse-type GC is more common in women and younger individuals; meanwhile, intestinal-type GC is more typically found in men and older individuals[5].

The risk factors for GC include genetic predisposition, age, sex, diet, obesity, smoking status, alcohol intake, Epstein-Barr virus infection, and H. pylori infection. Among these, H. pylori is the main risk factor and is responsible for most GC cases worldwide[4,6]. This bacterium causes chronic inflammation of the stomach that leads to GC through a serial step-by-step progression known as Correa’s cascade, which involves a transition from normal stomach tissue to atrophic gastritis, intestinal metaplasia, dysplasia, and finally invasive adenocarcinoma[7].

Owing to the absence of early-stage symptoms and the nonspecific nature of advanced-stage symptoms, GC is usually diagnosed in advanced stages, meaning that approximately 60% of patients are not eligible for curative treatment[3]. Although early-stage patients are eligible for surgery, which is sometimes combined with chemotherapy before or after surgery, for unresectable advanced-stage patients, chemotherapy is the main treatment used to prevent disease progression for as long as possible[8]. Overall, patients diagnosed with GC have a 28.3% 5-year survival rate[7], which underscores the importance of developing new treatment strategies for this disease.

Drug repurposing has emerged as a promising strategy for GC treatment. Drug repurposing consists of the use of already clinically approved drugs for new applications[9]. This can be accomplished through computational and experimental methods, although the most typical approach involves complementary use of these strategies[10,11].

Moreover, drug repurposing offers several advantages over traditional drug discovery methods, including reduced time and cost. De novo drug discovery is a highly expensive and risky process; it may take 10-15 years and cost more than 1 billion United States dollars, but only approximately 1% of compounds reach clinical trials. Drug repurposing significantly reduces these numbers, as the drugs have already undergone preclinical and clinical trials, and information about the drug compounds is already available[10,12]. In this review, we explore key molecular pathways involved in GC pathogenesis and explore potential drug repurposing opportunities targeting them.

PRENEOPLASTIC GASTRIC LESIONS

Correa’s cascade is a model of gastric carcinogenesis which proposes that intestinal-type GC arises as a result of a gradual change in the gastric mucosa. Normal gastric tissue transitions to non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, low-grade dysplasia, high-grade dysplasia, and finally adenocarcinoma[7]. Each stage presents distinct molecular alterations that can lead to progression to the next stage[13].

Gastritis

The starting point of Correa’s cascade is chronic inflammation of the stomach, known as gastritis, which is often related to H. pylori infection[14,15] and can evolve into atrophic gastritis after the loss of gastric glands. The bacterium liberates toxins such as CagA that produce inflammation and dysregulate the molecular landscape of the stomach[13].

Several pathways are involved in the development of chronic atrophic gastritis. The nuclear factor kappa B (NF-κB) signaling pathway is closely related to inflammation and malignancies; thus, this pathway could represent a target for reversing damage to the gastric mucosa. Hedgehog signaling is also relevant, as its loss indicates the progression of chronic atrophic gastritis to subsequent stages[16].

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin signaling pathways are also activated by H. pylori infection and are associated with disease progression[16]. In fact, a recent study showed that H. pylori activates the Wnt/β-catenin pathway in a mouse model and that the use of MoLuoDan, a traditional Chinese medicine, may inhibit this pathway and reverse some molecular damage present in gastritis[17].

Another relevant pathway is associated with the tumor suppressor p53, which is degraded during H. pylori infection via AKT1. The gene encoding this protein, TP53, has been found to be mutated as early as the gastritis phase[18].

Finally, the effects of the Hippo pathway on the development of gastritis are contradictory, with studies indicating both induction and protection from metaplasia due to its activation[16,19].

Intestinal metaplasia

Intestinal metaplasia is the next step in the GC cascade and is characterized by loss of the gastric epithelium and its transformation into an intestinal epithelium[14]. Intestinal metaplasia is already considered a precancerous lesion, greatly increasing the risk of GC, and it seems to be an irreversible point in the precancerous cascade[20,21].

Bile acids are important factors in the development of intestinal metaplasia, even in the absence of H. pylori[15,22], and one mechanism of action is the activation of the NF-κB signaling pathway[22]. Other pathways involved include Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3)[21], MAPK, and other molecular pathways involved in intestinal development such as the Wnt and Hedgehog pathways[20].

Several compounds have demonstrated efficacy in treating intestinal metaplasia. Mitogen-activated protein (MEK) inhibitors have been shown to reduce growth and signs of dysplasia in mouse organoid models[23]. Meanwhile, resveratrol, a natural compound that is present in the traditional Chinese medicine Polygonum cuspidatum, has been shown to inhibit the expression of metaplasia markers via regulation of the PI3K-AKT signaling pathway[24].

Dysplasia

In the dysplastic stage, the epithelium shows typical characteristics of neoplasia but no evidence of lamina propria invasion. Dysplasia is classified as either low-grade dysplasia, in which the architecture and features of the cell are more preserved, or high-grade dysplasia, in which a more atypical structure is observed. In high-grade dysplasia, complex glandular architecture and cytologic atypia with marked nuclei and large nucleoli are present along with a loss of cell polarity and high mitosis rates[14].

With respect to dysregulated pathways, evidence has shown that yes-associated protein (YAP), one of the main proteins in the Hippo signaling pathway, is overexpressed in high-grade dysplasia, and its crosstalk with the Wnt pathway has been connected to chemoresistance in GC[19]. The p53 pathway is also relevant at this stage, as approximately 88% of dysplasia samples have mutations in TP53[13], and inhibition of the NF-κB signaling pathway seems to promote dysplasia development[16]. Other important pathways include the MAPK and STAT3 pathways. These pathways have been shown to be inhibited by pyrvinim, which is effective against dysplastic cells[25].

CURRENT TREATMENT FOR GC

GC is defined by the penetration of neoplastic cells into the surrounding stroma through degradation of the stromal matrix. Depending on the depth of invasion of the gastric wall, GC can be classified as early, when it is limited to the mucosa or superficial submucosa, or advanced[7,14], when the neoplastic cells have invaded the deep submucosal layer or beyond, with subsequent distant dissemination potential.

Current European clinical guidelines consider three types of treatment according to the stage at diagnosis. Early-stage GC is treated with endoscopic resection, whereas for advanced stages, a combination of surgery and perioperative chemotherapy is the standard. Finally, in the case of advanced metastatic cancer, different lines of chemotherapy are applied with the goal of prolonging survival and improving the quality of life of patients[3,5,26].

Early GC treatment

According to European guidelines, early-stage IA cancers can be treated with either endoscopic or surgical resection, depending on whether deep submucosal infiltration exists. Survival rates at this stage are relatively high, and chemotherapy is not a standard treatment, as no benefit has been demonstrated[5].

Advanced GC treatment

From stages IB to III, surgical resection is the typical treatment for GC, but neoadjuvant (before surgery) and adjuvant (after surgery) chemotherapy may be added[26,27]. Although some Asian clinical guidelines do not have a strong recommendation for neoadjuvant chemotherapy, in Europe, the application of both (called perioperative chemotherapy) is standard[3,28]. European guidelines recommend four cycles of preoperative and postoperative 5-fluorouracil-leucovorin-oxaliplatin-docetaxel for patients who are able to tolerate that treatment, which includes a fluoropyrimidine, a platinum compound, and docetaxel. For unfit patients, a modified regimen may be administered that includes a reduced dose or a platinum and fluoropyrimidine doublet[3,26].

In stage IV patients, median survival is low, but chemotherapy has been shown to prolong survival and quality of life[5]. First-line chemotherapy commonly includes a combination of a platinum drug and a fluoropyrimidine. Complementary therapy is used for human epidermal growth factor receptor 2-positive (HER2 +) and programmed cell death ligand 1-positive patients, with the addition of trastuzumab and nivolumab/pembrolizumab, respectively, being beneficial[3,5].

For second-line therapy, paclitaxel, docetaxel, and irinotecan are used, sometimes with the addition of ramucirumab or immunotherapy. Finally, oral treatment with trifluridine and tipiracil is a typical third-line treatment, although taxane and irinotecan can also be considered[26]. Gastrectomy is generally not recommended for advanced metastatic stages[3].

POTENTIAL TARGETS FOR DRUG REPURPOSING IN GC

Drug repurposing is becoming an important part of drug development because of its lower costs and reduced risks, and several pathways may be targeted for the treatment of GC[8,29]. These pathways include the MAPK, PI3K/AKT/mTOR, p53, JAK2/STAT3, hypoxia-inducible factor-1α (HIF-1α), Wnt/β-catenin, NF-κB, and Hippo signaling pathways. A summary of the drugs and their target pathways is presented in Table 1.

Table 1 Candidates for drug repurposing in gastric cancer and target pathways[29-41,43-67,70-80,83,84,86-98,101-107,110-113].

Drug	Type	Approved use	Target pathway(s)/molecule(s)	Effects	Ref.
Doxycicline	Antibiotic	Bacterial infection	MAPK, Wnt	Inhibit proliferation, colony formation, and spheroid growth	Magnelli et al[30]; Pandian et al[31]
Lovastatin	Statin	Lower cholesterol	MAPK	Inhibit growth, increase sensitivity of anti-HER2 therapy, radioprotective effects in healthy tissues	Gao et al[32]; Zhang et al[33]; Du et al[34]; Rao et al[35]
Silymarin	Natural product	Epilepsy and hepato-protection	MAPK	Inhibit growth and proliferation in vivo and in vitro	Koltai and Fliegel[36]; Kim et al[37]
Tegaserod	5-HTR4 receptor agonist	Irritable bowel syndrome	MAPK	Inhibit growth in vivo and in vitro	Chen et al[38]; Wang et al[39]
Trametinib	MEK inhibitor	Melanoma	MAPK	Suppress tumor development and liver metastasis in mouse organoids	Yamasaki et al[40]; Wang et al[41]
ATRA	Ligand for retinoic acid and retinoic X receptor	Promyelocytic leukemia	PI3K, Wnt	Suppress proliferation in vivo and in vitro	Bouriez et al[43]; Zhang et al[44]; Jin et al[45]
Danusertib/alisertib	Aurora kinase inhibitors	Not approved (phase II for prostate cancer and phase III for lymphoma, respectively)	MAPK	Inhibit proliferation, induce cell cycle arrest, and promote apoptosis and autophagy	Yuan et al[46]; Yuan et al[47]; Novais et al[48]
Deferasirox	Iron chelator	Iron overload disease	mTOR	Induce apoptosis	Choi et al[49]
Dronedarone	Antiarrhythmic	Auricular fibrillation	PI3K	Suppress cell proliferation and colony formation	Lu et al[50]; CIMA[113]
Metformin	Biguanide	Type 2 diabetes	PI3K	Induce apoptosis in vitro	Lu et al[51]; Lan et al[52]; Hu et al[53]
Mycophenolic acid	IMPDH inhibitor	Organ transplant, lupus eritrematosus	PI3K	Inhibit proliferation	Hsieh et al[54]; Dun et al[55]
Naftopidil	Α-1-adrenoceptor blocker	Benign prostate hyperplasia	PI3K	Induce apoptosis	Nakamura et al[56]; Kaku et al[57]; Florent et al[58]
Rapamycin	mTOR inhibitor	Organ transplant	mTOR, HIF-1α	Reduce cell proliferation and invasiveness	Chen et al[59]; Morgos et al[60]; Liu et al[61]; CIMA[113]
Sertraline	Antidepressant (SSRI)	Depression in cancer patients	PI3K, HIF-1α	Resensitize drug resistant GC	Mu et al[62]; Sánchez-Castillo et al[63]; Sun et al[64]; Wang et al[65]
Vortioxetine	Antidepressant	Depression	PI3K, JAK2/STAT3	Inhibit cell proliferation, migration, and invasion and induce apoptosis and autophagy	Chen et al[38]; Lv et al[66]; Li et al[67]
Thioridazine	Antipsychotic	Schizophrenia	PI3K, Wnt	Reduce cell viability, induce apoptosis, and enhance anti-HER2 therapy	Yang et al[70]
Tigecycline	Antibiotic	Complicated infections	PI3K	Induce autophagy and inhibit cell proliferation	Dong et al[71]; Tang et al[72]
Valproic acid	HDAC1/2 inhibitor	Bipolar disorder, epilepsy	PI3K	Induce apoptosis	Zhang et al[33]; Fushida et al[73]; Sun et al[74]
Econazole	Antifungal	Skin infections	p53, PI3K	Caspase-dependent apoptosis (p53 activation); inhibit metastasis (MMP2/9)	Choi et al[75]
Bazedoxifene	Estrogen receptor modulator	Postmenopausal osteoporosis	JAK2/STAT3	Reduce tumor burden	Thilakasiri et al[76]; Wu et al[77]
Fedratinib	JAK2 inhibitor	Myelofibrosis	JAK2/STAT3	Inhibit cell proliferation	Wang et al[41]; Passamonti et al[78]; Miyazaki et al[79]; Mao et al[80]
Disulfiram	Acetaldehyde dehydrogenase inhibitor	Alcohol abuse	Wnt, NF-κB, MAPK	Inhibit proliferation and induce apoptosis	Zhang et al[86]; Liu et al[87]
Propofol	Sedative-hypnotic	Anesthesia	Wnt, JAK2/STAT3	Inhibit cell growth, invasion, and migration	Zhan et al[88]; Chen et al[89]
Tipifarnib	Farnesyltransferase inhibitor	Not approved (phase II for HNSCC)	mTOR, HIF-1α	Inhibit proliferation and migration	Egawa et al[83]; Zhou et al[84]
Simvastatin	Statin	Lower cholesterol	Wnt, Hippo	Inhibit proliferation and metastasis and reduce radiotoxicity of healthy tissues	Rao et al[35]; Liu et al[90]
Bortezomib	Proteasome inhibitor	Multiple myeloma	NF-κB	Inhibit growth and induce apoptosis	Guo et al[91]; Nakata et al[92]; Ocean et al[93]; Bui et al[94]
Propranolol	β-AR receptor blocker	Cardiovascular diseases, postmenopausal osteoporosis	NF-κB	Increase sensitivity to chemotherapy, cell cycle arrest, apoptosis, and inhibit tumor growth in xenograph models	Liao et al[95]; Koh et al[96]
Resveratrol	Natural product	Metabolic and cardiovascular diseases	NF-κB	Decrease cell viability	Trautmann et al[97]; Rojo et al[98]
Verteporfin	Benzoporphyrin	Photodinamic therapy	Hippo	Inhibit cell proliferation	Giraud et al[101]
Abacavir	Nucleoside reverse transcriptase inhibitor	HIV infection	TERT	Insufficiently suppress cell proliferation and activate tumorigenic pathways	Panneerpandian et al[102]
Candesartan	Angiotensin II type I receptor blocker	Hypertension, heart failure, diabetic neuropathy	TGF-β1	Suppress tumor cell proliferation and stromal fibrosis in xenograph models	Araújo et al[29]; Okazaki et al[103]
Telmisartan	Angiotensin II type I receptor blocker	Hypertension, heart failure, diabetic neuropathy	EGFR	Inhibit proliferation	Araújo et al[29]; Fujita et al[104]
Fluoxetine	Antidepressant	Depression in cancer patients	Death receptor pathway	Induce apoptosis	Araújo et al[29]; Po et al[105]
Itraconazole	Antifungal	Fungal infections	Hedgehog	Inhibit proliferation and increase apoptosis	Hu et al[106]
Levobupivacaine	Local anesthetic	Anesthesia	Ferroptosis	Inhibit growth in vitro and in vivo and induce ferroptosis	Mao et al[107]
Paroxetine	Antidepressant (SSRI)	Depression	DNA repair proteins	Induce apoptosis and inhibit cell viability	Liu et al[110]; Kowalska et al[111]
Risperidone	Antipsychotic	Schizophrenia	Unknown (proposed: Histone deacethylation, dopamine receptor and cholesterol homeostasis)	Induce apoptosis and inhibit growth	Chen et al[112]

ATRA: All-trans retinoic acid; SSRI: Serotonin reuptake inhibitor; β-AR: Beta-adrenergic receptor; JAK2: Janus kinase 2; HDAC1/2: Histone deacetylase 1/2; mTOR: Mammalian target of rapamycin; IMPDH: Inosine monophosphate dehydrogenase; MEK: Mitogen-activated protein; 5-HTR4: 5-hydroxytryptamine receptor 4; HNSCC: Head and neck squamous cell carcinoma; HIV: Human immunodeficiency virus; MAPK: Mitogen-activated protein kinase; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; HIF-1α: Hypoxia-inducible factor-1α; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; TERT: Telomerase reverse transcriptase; TGF-β1: Transforming growth factor-β1; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; GC: Gastric cancer; MMP: Matrix metalloproteinase.

MAPK signaling pathway

MAPKs are a family of serine/threonine kinases that regulate different functions in GC, such as proliferation, migration, invasion, and metastasis. The signaling pathway is composed of five cascades: The Jun amino-terminal kinases cascade, the p38/MAPK cascade, and three extracellular signal-regulated kinase (ERK) cascades. One of the most relevant cascades is the ERK/MAPK cascade. ERK/MAPK controls matrix metalloproteinases (MMPs), which are proteins that degrade the extracellular matrix and play a role in cell migration and invasion. The signaling cascade starts with RAS, which interacts with RAF. This activates MEK1/2 kinases, which in turn activate ERK[8,30]. MAPK/ERK signaling is deregulated in approximately one-third of human cancers, and inhibitors of this pathway have been shown to be effective against GC[30,31] (Figure 1).

Figure 1 Mechanisms of action of repurposed drugs targeting the mitogen-activated protein kinase signaling pathway. Purple form indicated main pathway proteins; light blue form indicated drugs; dark blue form indicated proteins involved in the mechanism of action of the drug; “?” symbol indicated target is not clear. KLF: Krupple-like factor; DDIT4: DNA damage inducible transcript 4; MEK: Mitogen-activated protein; ERK: Extracellular signal-regulated kinase; MAPK: Mitogen-activated protein kinase.

Twenty-six antimicrobial agents were screened in a GC cell line to study their role as ERK/MAPK inhibitors, and among them, doxycycline had strong inhibitory effects. This drug is an antibiotic whose mechanism of action consists of binding with the 30S ribosomal subunit and interfering with translation. Doxycycline has already been shown to have anticancer effects on breast and prostate cancers. In GC, doxycycline inhibits proliferation, colony formation, and spheroid growth[31]. Moreover, the compound also inhibits several pathways expressed in a subset of GCs, such as the Wnt signaling pathway[30].

Lovastatin is a statin typically used to lower cholesterol levels that has shown anticancer effects in breast cancer, ovarian cancer, and multiple myeloma[32]. Lovastatin has been identified as a promising drug for treating GC because of its ability to inhibit the growth of GC cells[33]. In leukemia, lovastatin inhibited leukemogenesis through the induction of Krupple-like factor 5 and subsequent downregulation of DNA damage inducible transcript 4 (DDIT4), which inhibited the MAPK pathway[32]. Given that DDIT4 has been shown to promote GC tumorigenesis through the MAPK and p53 pathways[34], this pathway could also be a potential target of lovastatin in GC. In addition, a recent study demonstrated that lovastatin increased the efficacy of anti-HER2 therapy in HER2 + GC patients when it was combined with trastuzumab. Lovastatin acts by increasing the availability of membrane-bound HER2 while simultaneously having radioprotective effects in normal tissues[35].

Silymarin, a product obtained from the milk thistle plant (Silybum marianum), has been used for the treatment of epilepsy and for hepatoprotection in patients with cirrhosis or alcoholic hepatitis, among other conditions[36,37]. In both in vitro and in vivo studies, silymarin inhibited growth and proliferation in both GC cells and tumor xenograft mouse models by downregulating the MAPK pathway[37].

Tegaserod is a 5-hydroxytryptamine receptor 4 (5-HTR4) agonist that is typically employed to treat irritable bowel syndrome[38]. In GC, the drug acts by inhibiting MEK1/2 kinases, whose high levels are correlated with poor patient prognosis. Their inhibition decreases ERK1/2 signaling and therefore inhibits GC growth in vitro and in vivo[39].

The MEK inhibitor trametinib is already used in patients with melanoma and has been demonstrated to be effective in GC mouse organoid models with KRAS mutations[40,41]. KRAS mutations are present in many human cancers and result in lower overall survival in patients with GC. They activate signaling pathways such as the PI3K and MAPK pathways. In a recent study, the use of trametinib in mouse organoid models reduced the number of phosphorylated ERK proteins and suppressed tumor development as well as liver metastasis[40]. However, in another study, trametinib alone was not enough to suppress the proliferation of GC cells, but combination therapy with the JAK2/STAT3 inhibitor fedratinib reduced cell survival and induced apoptosis[41].

PI3K/AKT/mTOR signaling pathway

The PI3K/AKT pathway is relevant in cancer and regulates the inhibition of apoptosis, the induction of drug resistance, metastasis, and angiogenesis[8,42]. Downstream signaling of PI3K results in the recruitment of the serine-threonine kinase AKT, which has mTOR as a downstream effector. Effective inhibitors could lead to better outcomes for cancer patients, and some have already been approved for clinical use[42] (Figure 2).

Figure 2 Mechanisms of action of repurposed drugs targeting the phosphoinositide 3-kinase, p53, and hypoxia-inducible factor-1α signaling pathways. Purple form indicated main pathway proteins; light blue form indicated drugs; dark blue form indicated proteins involved in the mechanism of action of the drug; “?” symbol indicated target is not clear. ATRA: All-trans retinoic acid; Pin1: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; AMPK: Adenosine 5’-monophosphate-activated protein kinase; SRC: Proto-oncogene tyrosine-protein kinase Src; DRD2: Dopamine receptor D2; HDAC1/2: Histone deacetylase 1/2; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; SMHT2: Serine hydroxymethyl transferase 2.

Retinoic acids are compounds derived from vitamin A and are ligands for retinoic acid receptors and retinoic X receptors. Both receptors form a heterodimer and act as transcription factors for proteins that play a role in cell differentiation[43]. All-trans retinoic acid (ATRA) is used to treat promyelocytic leukemia and has been previously reported to exert antitumor effects in other cancers, such as breast and liver cancer, through the inhibition of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1. This protein is also confirmed to be a target in GC cells, suppressing proliferation in vivo and in vitro. The protein is involved in the PI3K and Wnt signaling pathways and in crosstalk between these pathways, both of which are highly relevant in GC[44]. In addition, ATRA affects gastric dysplasia. The addition of omeprazole and sucralfate to conventional treatment for gastritis has been shown to improve the prognosis of patients with gastric dysplasia by increasing retinoblastoma levels and reducing HER2 levels[45]. ATRA also has two isomers, 13-cis-retinoic acid and 9-cis-retinoic acid, which have anticancer effects on GC. However, these isomers are too toxic for use in GC patients[43].

Aurora kinases are important regulators of mitosis, and their overexpression promotes the development of GC. As such, they have been proposed as promising targets[46]. Danusertib and alisertib are aurora kinase inhibitors; danusertib is a pan-inhibitor and alisertib specifically inhibits aurora kinase A. Studies in GC cell lines have shown that both compounds inhibit cell proliferation, induce cell cycle arrest, and promote apoptosis and autophagy. These compounds exert their effects through adenosine 5’-monophosphate-activated protein kinase (AMPK) and p38-MAPK, which are upstream regulators of AKT/mTOR[46,47]. Although not approved, danusertib and alisertib have passed phase II clinical trials, and alisertib has a single completed phase III trial in peripheral T-cell lymphoma. A trial of danusertib as a single agent in hormone-refractory prostate cancer patients showed no objective response, but alisertib has shown some efficacy in combination therapy for solid and hematological tumors[48].

Deferasirox is an iron chelator used for the treatment of iron overload disease. Iron chelators are being explored as anticancer agents because iron metabolism is implicated in tumor initiation and growth. Despite adverse events such as gastrointestinal disturbance or renal toxicity, deferasirox is generally well tolerated and has been shown to have antineoplastic effects on leukemias through downregulation of the NF-κB and mTOR pathways. In GC, deferasirox induces apoptosis and exerts its antitumor effects through several pathways, which include the inhibition of cell cycle progression and effects on the mTOR and metastasis pathways[49].

Dronedarone hydrochloride is an antiarrhythmic drug that targets the proto-oncogene tyrosine-protein kinase Src (SRC). This kinase regulates processes such as proliferation, migration, and invasion and plays a role in tumorigenesis by phosphorylating AKT1. In GC, cell proliferation and colony formation were suppressed in cells treated with dronedarone. The mechanism of action consists of the drug binding to and inhibiting SRC activity, thereby downregulating the AKT signaling pathway[50].

Metformin is used for the treatment of type 2 diabetes and is associated with a decreased risk of cancer. Metformin acts by suppressing respiratory complex I, which results in the activation of AMPK signaling, reducing blood glucose levels and enhancing insulin sensitivity. Metformin has been shown to induce the apoptosis of GC cells in vitro through this mechanism, as treatment with metformin resulted in the upregulation of AMPK. In turn, this protein modulates the PI3K/AKT pathway[51]. Interestingly, metformin is not only a promising treatment for GC but also a promising preventive agent. Metformin was shown to reduce GC risk[52] and had therapeutic effects in an intestinal metaplasia mouse model[53].

Mycophenolic acid is an inhibitor of inosine monophosphate dehydrogenase, which reduces de novo purine synthesis, inhibiting T and B lymphocytes. Therefore, mycophenolic acid results in immunosuppression and, as such, is used for applications such as organ transplantation and lupus erythematosus[54,55]. In GC, mycophenolic acid has been shown to decrease AKT activity by reducing its phosphorylation, which reduced the capacity for proliferation of GC cells.

Naftopidil is a drug used for the treatment of benign prostate hyperplasia that acts by blocking the α-1 adrenoceptor. Naftopidil has been shown to reduce prostate cancer risk and induce death in these cancer cells. In GC cells, naftopidil induces apoptosis through the inhibition of the PI3K/AKT signaling pathway by reducing the phosphorylation levels of AKT, and treatment with naftopidil plus an autophagy inhibitor enhances its apoptotic effects[56]. In a previous study, a synthetic analogous compound of naftopidil was shown to have an even stronger effect for suppressing cell proliferation in GC cells[57]. However, the application of naftopidil is approved only in Japan, and clinical trials have been performed only in Asian populations, which present some metabolic differences compared with non-Asian populations. In addition, naftopidil has not been tested in women, so further information about its safety is needed[58].

Rapamycin is an mTOR inhibitor and can reduce the proliferation and invasion of GC cells. As HIF-1α is downstream of mTOR, rapamycin can also inhibit HIF-1α- and HIF-1-dependent transcription induced by hypoxia[59,60]. An analogous compound, 42-(2-tetrazolyl) rapamycin, was shown to inhibit Forkhead box protein P4, downregulating the Hippo pathway. This suppressed tumor growth and increased the efficacy of the chemotherapeutic drug 5-fluorouracil that is used in standard treatment[61].

Sertraline is an antidepressant of the serotonin reuptake inhibitor (SSRI) type, and the use of SSRIs has been shown to prolong survival and quality of life in cancer patients with depression. Sertraline has been shown to resensitize drug-resistant GC through the induction of apoptosis via the PI3K pathway. The effects of normal sertraline are limited; thus, modified sertraline derivatives have been used with better results[62]. Sertraline has also been shown to have an effect on non-small cell lung cancer, in which the target is serine hydroxymethyl transferase 2[63]. Given that this target has been shown to upregulate the PI3K signaling pathway[64] and is upregulated in GC and other cancers (in which it regulates other pathways, such as the HIF-1α pathway[65]), this is a plausible mechanism of action in GC.

Vortioxetine is another antidepressant that affects the serotonin pathway by inhibiting 5-HTR3A[38]. A recent study revealed that vortioxetine could inhibit cell proliferation, migration, and invasion in a GC cell line. Vortioxetine induced apoptosis and autophagy in cells via the PI3K pathway by decreasing the phosphorylation levels of AKT and mTOR[66]. Another study revealed that vortioxetine exerts anticancer activity by directly binding to JAK2 and SRC, which inhibits them and thus inhibits the JAK2/STAT3 signaling pathway[67].

Thioridazine is an antipsychotic drug with reported effects on different cancers, including leukemia and breast cancer. In GC cells, thioridazine has been shown to reduce cell viability and induce cell apoptosis via the inhibition of dopamine receptor D2 (DRD2), a receptor that controls AKT and Wnt. Therefore, the observed effects could be related to these pathways[68]. A posterior analysis of 84 GC samples revealed the relevance of DRD2 in GC; higher levels of this receptor were found in GC and patients with higher levels of DRD2 had a worse prognosis[69]. Another interesting point in favor of repurposing thioridazine against GC was demonstrated in a recent study in which the therapeutic effect of anti-HER2 chemotherapy was enhanced when this drug was combined with thioridazine. This was mediated through the inhibition of S-phase kinase associated protein 2 (Skp2), a component of the Skp2-stem cell factor complex. This complex plays a role in ubiquitination, cell cycle progression, proliferation, and apoptosis[70].

Tigecycline is a glycilcycline-type antibiotic that is used to treat complicated infections and has shown important anticancer effects on solid and liquid tumors[71]. An in vitro study revealed that tigecycline induced autophagy and inhibited cell proliferation in GC cells through the upregulation of AMPK, which led to the inhibition of the PI3K signaling pathway[72].

Valproic acid is a histone deacetylase inhibitor that is used to treat bipolar disorder and epilepsy[73]. High expression of the drug’s target, histone deacetylase 1/2, has been linked to poor survival in patients with GC. Through this target, valproic acid downregulates the activity of the PI3K signaling pathway by inhibiting AKT, which results in apoptosis in GC cells. The main disadvantage is that the therapeutic concentrations reached in in vitro experiments are not achievable in the clinic; thus, other strategies such as a combination of valproic acid with chemotherapy should be used[74]. Another study reported similar results in different GC cell lines[33]. However, the drug has already been tested in a phase II clinical trial to determine whether it offered survival advantages in advanced GC when combined with paclitaxel, compared with paclitaxel alone, and negative results were obtained[73].

p53 signaling pathway

The p53 signaling pathway is involved in the regulation of DNA repair and control of the cell cycle, apoptosis, and differentiation. This pathway can block the cell cycle in vertebrates by controlling checkpoints in the G1/S and G2/M phases; thus, its function is related to cyclins and cyclin-dependent kinases. More than 75% of GC patients have elevated levels of p53. H. pylori infection can induce mutations in the TP53 gene, so inhibition of this pathway may be a therapeutic strategy for this stage[8] (Figure 2).

Econazole is an antifungal drug and a calcium ion channel agonist that is used for the treatment of skin infections. According to a recent study, this drug activates p53 and induces caspase-dependent apoptosis in GC cells. Moreover, econazole affects different signaling pathways, producing decreased levels of phosphorylated PI3K, AKT, and ERK. Downregulation of MMP2 and MMP9 has also been shown, which inhibits the metastatic capacity of the cells[75].

JAK2/STAT3

STAT3 is an oncogene that is overexpressed in many cancers, including GC. The JAK2/STAT3 signaling pathway is triggered by the binding of an interleukin (IL) or an elongation factor G family member to transmembrane cytokine receptors. After that, the JAK2 receptor is dimerized and transphosphorylated, which activates STAT3. STAT3 is subsequently translocated to the nucleus, where it acts as a transcription factor that regulates (among other genes) genes related to cancer cell growth, tumor invasion, and chemoresistance. In GC, STAT3 signaling has been linked to tumor progression and metastasis[8] (Figure 3).

Figure 3 Mechanisms of action of repurposed drugs targeting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. Purple form indicated main pathway proteins; light blue form indicated drugs; dark blue form indicated proteins involved in the mechanism of action of the drug; IL11: Interleukin 11; JAK2: Janus kinase 2; STAT3: Signal transducer and activator of transcription 3.

Bazedoxifene is a selective estrogen receptor modulator used for the treatment and prevention of postmenopausal osteoporosis. This drug has demonstrated antitumor effects in pancreatic cancer and other gastrointestinal cancers[76,77]. In mouse models of gastrointestinal cancers, bazedoxifene reduced the tumor burden and interfered with the binding of IL-11 to the receptor β subunit gp130, which inhibited JAK2/STAT3. In addition, as the mechanism of action is independent of the modulation of the estrogen receptor, bazedoxifene has been shown to have the same tumor burden-reducing effect in males and females[76].

Fedratinib is a JAK2-selective inhibitor that is approved for the treatment of myelofibrosis[78]. When applied in combination with other drugs, it has anticancer effects on pancreatic cancer and colorectal cancer[79,80]. In fact, high doses of the drug have been reported to have serious adverse effects; thus, its combination with other drugs could enable the use of a lower dose[79]. In a recent study, fedratinib was tested alone and in combination with the MEK inhibitor trametinib. Although fedratinib had a stronger inhibitory effect on GC than trametinib when both were applied alone, their combination had an even stronger effect, and the combination had similar effects on pancreatic cancer[41].

HIF-1α

The HIF family genes include HIF-1, HIF-2, and HIF-3. HIF-1 is composed of two subunits, HIF-1α and HIF-1β. Under normoxic conditions, HIF-1α is degraded, but under hypoxic conditions, HIF-1α enters the nucleus and combines with HIF-1β to promote gene transcription. These genes play important roles in cancer, especially HIF-1α, which inhibits apoptosis and promotes processes such as proliferation, metastasis, drug resistance, and angiogenesis in GC[81]. In fact, HIF-1α not only contributes to tumor progression but also to the carcinogenetic process, as HIF-1α expression increases with progression through Correa’s cascade. The frequency of HIF-1α positivity is greater in diffuse-type GC than in intestinal-type GC; thus, HIF-1α likely plays an even more important role in this type of cancer. This pathway also interacts with others, and the upregulation of MAPK and PI3K potentiate HIF-1α activity, which indicates that the inhibition of these pathways could also inhibit HIF-1α[82] (Figure 2).

A drug that targets this pathway, tipifarnib, is a farnesyltransferase inhibitor. This drug was granted fast track designation by the United States Food and Drug Administration for the treatment of head and neck squamous cell carcinoma in 2019 after positive results were obtained in a phase II clinical trial, and tipifarnib has already demonstrated its efficacy in triple-negative breast cancer[83,84]. Low doses have been tested in GC cell lines, and tipifarnib inhibited the proliferation and migration of HIF-1α-positive cells but had no effect on a HIF-1α-negative cell line. The mechanism of action involves the inhibition of Rheb farnesylation, which suppresses the mTOR/HIF-1α signaling pathway[83].

Wnt/β-catenin signaling pathway

The Wnt signaling pathways include the classical Wnt/β-catenin pathway, which is involved in cell proliferation, and the nonclassical Wnt/planar cell polarity and Wnt/calcium ion pathways, which are involved in cell polarity and migration. β-catenin is a transcriptional coactivator involved in proliferation, apoptosis, and infiltration in tumor cells. Dysregulation of the Wnt/β-catenin signaling pathway is present in more than half of GC patients and is related to treatment resistance and epithelial–mesenchymal transition[8,85] (Figure 4).

Figure 4 Mechanisms of action of repurposed drugs targeting the Wnt, nuclear factor kappa B, and Hippo signaling pathways. Purple form indicated main pathway proteins; light blue form indicated drugs; dark blue form indicated proteins involved in the mechanism of action of the drug; “?” symbol indicated target is not clear. β-AR: Beta-adrenergic receptor; NF-κB: Nuclear factor kappa B; DKK1: Dickkopf-related protein 1; YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; HMGCR: Hydroxymethyl glutaryl-CoA.

Disulfiram is a drug that is used to treat alcohol abuse through the inhibition of acetaldehyde dehydrogenase. Disulfiram has been shown to have anticancer effects and to reverse drug resistance, inhibit DNA methylation, and induce apoptosis. In a recent study, disulfiram inhibited proliferation in two GC cell lines and downregulated the Wnt and NF-κB signaling pathways[86]. Another possible mechanism of action depends on the presence of cupric ions. Disulfiram is catalyzed into diethyldithiocarbamate, which chelates into complexes that contain cupric ion. These factors enhance the antitumor properties of these compounds by increasing the level of cellular reactive oxygen species, which leads to apoptosis through the MAPK signaling pathway[86,87].

Propofol is a sedative-hypnotic drug that is used for anesthesia, and its use in the surgical resection of tumors has been shown to reduce the likelihood of recurrence. Propofol has been reported to inhibit GC cell growth, invasion, and migration through increased expression of miR-493-3p. This microRNA (miRNA) targets Dickkopf-related protein 1 (DKK1), an activator of the Wnt signaling pathway, whose high expression has been linked to poor survival in GC patients. Increased expression of this miRNA decreases the expression of DKK1 and inhibits the Wnt signaling pathway[88]. Propofol has also been shown to upregulate the expression of other miRNAs, such as miR-125b-5p, which inhibits the JAK2/STAT3 signaling pathway[89].

Like other statins, simvastatin is used to decrease blood cholesterol levels by inhibiting hydroxymethylglutaryl-CoA reductase. This target protein is upregulated in GC and is related to cancer cell growth and migration. In one study, the mechanism of action was proposed to involve targeting hydroxymethylglutaryl-CoA, which downregulates geranylgeranyl pyrophosphate. This is necessary for the posttranslational modification of RhoA, so this process reduces active RhoA levels and decreases the levels of β–catenin and YAP. In addition, a positive feedback loop was found to exist between YAP and Wnt, despite previous findings that Hippo inhibits Wnt. Therefore, simvastatin was found to inhibit proliferation and metastasis via this mechanism[90]. Another point in favor of repurposing this drug for GC treatment is its ability to reduce radiotoxicity in normal tissues (similar to lovastatin and other statins)[35].

NF-κB

NF-κB is a family of transcription factors comprising RelA, V-Rel reticuloendotheliosis viral oncogene homolog B, c-Rel, NF-κB1, and NF-κB2. NF-κB can be activated by tumor necrosis factor receptors, toll-like receptors, and the IL-1 receptor. Under normal conditions, NF-κB remains in the cytoplasm in an inactive state and is bound to a family of proteins called inhibitor of NF-κB (IκB). However, when the IκB kinase complex is stimulated, the transcription factor is liberated and translocated to the nucleus where it promotes the transcription of different target genes, and thus the progression of GC[8]. In cancer, NF-κB is aberrantly activated, which leads to tumor proliferation, the inhibition of apoptosis, and the facilitation of metastasis[91] (Figure 4).

Bortezomib is a selective and reversible proteasome inhibitor that inhibits the activity of the 26S proteasome, which functions in protein degradation[91]. This drug is approved for treatment of multiple myeloma, and a previous study showed that bortezomib inhibited growth and induced apoptosis in seven GC cell lines and in vivo xenograft models. Its effect occurred through the inhibition of NF-κB, and it had a greater effect on cell lines with lower levels of NF-κB[92]. In contrast, in a clinical trial of bortezomib alone and in combination with irinotecan in advanced gastroesophageal junction and gastric adenocarcinoma, bortezomib alone had limited effects and did not enhance the effectiveness of irinotecan[93]. However, a recent study revealed that it could overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance. TRAIL is a compound that causes apoptosis in many cancer cell types, including GC, but resistance to treatment with TRAIL has been observed. The application of bortezomib caused cell cycle arrest and apoptosis, and these effects were thought to be mediated by the upregulation of dopamine receptor 5[94].

Propranolol is a nonselective β-adrenergic receptor (β-AR) blocker that is used to treat cardiovascular diseases and other conditions such as post-menopausal osteoporosis. In addition, propranolol has been shown to have anticancer effects for neuroblastoma and GC. β-AR inhibition has been shown to increase the sensitivity of cancer cells to radiotherapy through NF-κB inhibition. Moreover, propranolol was shown to reduce the side effects of radiation on surrounding tissues[95]. Another study revealed that propranolol caused cell cycle arrest and apoptosis in GC cell lines and also affected metastasis by suppressing the expression of MMP2, MMP9, and vascular endothelial growth factor A. These effects were consistent with those in xenograft mouse models, in which tumor growth was inhibited[96].

Resveratrol is a natural polyphenol that is present in foods such as nuts, apples, and black olives. This polyphenol can interact with reactive oxygen species and cytoplasmic and nuclear proteins in cells, thus conferring its antioxidant, anti-inflammatory, and antimicrobial properties. These characteristics have made resveratrol an alternative and complementary therapy for metabolic and cardiovascular diseases, and it has also been shown to be useful for treating GC[97]. The antitumor effects of resveratrol are exerted partly through inhibition of the NF-κB signaling pathway. In a recent study, resveratrol was tested in two GC cell lines and was shown to decrease cell viability in a dose-dependent manner; cytotoxic effects occurred at higher concentrations and inhibition of the invasion potential of cells occurred at noncytotoxic concentrations. The proposed mechanism of action was the inhibition of heparanase as a result of the downregulation of NF-κB signaling. Heparanase plays an important role in the metastatic process of GC[98]. In addition, resveratrol has synergistic effects with some currently used chemotherapeutic agents such as 5-fluorouracil[97].

Hippo pathway

The Hippo signaling cascade starts with mammalian sterile20-like kinases 1/2 phosphorylating large tumor suppressor 1/2 kinases. These phosphorylate the transcription coactivators YAP/transcriptional coactivator with PDZ-binding motif (TAZ), which are taken to the cytoplasm and degraded. However, when no Hippo signaling occurs, these proteins translocate to the nucleus and form a complex with the TEAD family. This promotes the expression of downstream target genes and, as a result, increases proliferation and decreases apoptosis. Current therapies focus on either suppressing YAP nuclear translocation by enhancing the Hippo pathway or disrupting the nuclear YAP/TAZ-TEAD complex[99] (Figure 4).

Therefore, the Hippo signaling pathway is considered a tumor-suppressor pathway that inhibits YAP/TAZ[19]. This pathway appears to be downregulated in GC, which indicates that YAP/TAZ and TEAD are upregulated; high YAP1 expression is associated with poor outcomes, promoting growth and metastasis[100]. In addition, YAP1 is overactivated in dysplasia and is involved in the processes stimulated by H. pylori that lead to carcinogenesis[19].

Verteporfin is a benzoporphyrin that is used in ophthalmology for photodynamic therapy, and its anticancer effects have been tested in breast, pancreatic, and GCs. In a recent study, YAP1 and TAZ1 were shown to be overexpressed in chemoresistant stem cells, and the effects of verteporfin were tested in GC cell lines. Verteporfin targets YAP1/TAZ and decreases the transcriptional activity of YAP/TAZ-TEAD and cell proliferation[101].

Others

Other important pathways and proteins can be targeted for GC treatment, such as reverse transcriptase, transforming growth factor-beta (TGF-β), epidermal growth factor receptor (EGFR), autophagocytosis, Hedgehog, ferroptosis, and even DNA repair protein expression (Figure 5).

Figure 5 Mechanisms of action of repurposed drugs with other target proteins/pathways. Purple form indicated main pathway proteins; light blue form indicated drugs; dark blue form indicated proteins involved in the mechanism of action of the drug; “?” symbol indicated target is not clear. ERK: Extracellular signal-regulated kinase; HIF-1α: Hypoxia-inducible factor-1α; NF-κB: Nuclear factor kappa B; TERT: Telomerase reverse transcriptase; TGF-β1: Transforming growth factor-β1; EGFR: Epidermal growth factor receptor; DR: Dopamine receptor.

Abacavir is a nucleoside reverse transcriptase inhibitor that is used to treat human immunodeficiency virus infection, and as such, it causes telomere shortening, chromosomal instability, and cell death. Telomerase reverse transcriptase is overexpressed in tumor tissues and thus represents an interesting target for anticancer therapies. However, a recent study revealed that abacavir did not have enough potential to suppress GC cells, even at high concentrations, and it activated several tumorigenic pathways, including the Wnt, ERK, HIF-1α, and NF-κB pathways[102].

Candesartan is an angiotensin II type I receptor blocker that is used to treat hypertension, heart failure, and diabetic nephropathy[29,103]. Angiotensin II has been linked to cancer progression, and the mechanism of action of its inhibitors consists of antagonizing the angiotensin II type 1 receptor[104]. Candesartan was tested in a GC cell line and in mouse xenograft models and was found to inhibit TGF-β1. In addition, candesartan suppressed tumor cell proliferation and stromal fibrosis in xenograft models[103]. The effects of TGF-β1 can differ depending on the cell type and physiological environment. In GC, TGF-β1 has been shown to inhibit proliferation in some cell lines, but other studies have shown that it can promote tumor growth. In addition, high expression of TGF-β1 in patients with GC has been linked to poor 5-year survival[8].

Another angiotensin receptor blocker is telmisartan, which is used for the same purposes as candesartan[29]. Telmisartan has been shown to be effective against a variety of cancers, including T-cell leukemia, esophageal adenocarcinoma, and hepatocellular carcinoma. This drug was tested in GC cell lines, and it inhibited proliferation through cell cycle arrest in the G0/G1 phase. The proposed mechanism of action is the inactivation of EGFR, which is observed at 24 hours after treatment but not at 48 hours, and the changes in the levels of some miRNAs[104]. EGFR, which is also known as HER1 and is overexpressed in GC, is part of the EGFR family, whose members participate in the regulation of tumor cell growth, proliferation, and migration[8].

The antidepressant fluoxetine is typically used to treat cancer-related depression. Fluoxetine has also been shown to have anticancer activity[105] and may be a promising candidate for drug repurposing[29]. According to a recent study, fluoxetine induces apoptosis through the death receptor pathway. However, fluoxetine also increases autophagocytosis, which can reduce apoptosis. The combination of fluoxetine and an autophagy inhibitor, 3-methyladenine, increased the apoptotic effect of fluoxetine. Considering that the mechanism of action of 3-methyladenine involves a reduction in AKT levels[105], the combination of fluoxetine with a PI3K inhibitor may be beneficial in GC treatment.

Itraconazole is an antifungal drug that inhibits endothelial cell proliferation and angiogenesis. Hedgehog signaling has been revealed to be overactivated in GC tissues, as shown by overexpression of the marker zinc finger protein Gli1 in GC tissues compared with adjacent normal tissues. Itraconazole inhibited proliferation and increased apoptosis in GC cells, and when it was used in combination with the chemotherapeutic agent 5-fluorouracil, the antiproliferative effects increased. The mechanism of action involves the inhibition of Gli1 and, as a result, the Hedgehog signaling pathway[106]. The Hedgehog pathway plays important roles in embryonic tissue development and in maintaining tissue homeostasis. Aberrant activation of this pathway is associated with carcinogenesis in medulloblastoma, non-small cell lung cancer, breast cancer, and GC[8,106].

Levobupivacaine is a local anesthetic that has been demonstrated to be effective against several cancers including GC and breast cancer. In one study, levobupivacaine inhibited GC cell growth in vivo and in vitro through the induction of ferroptosis. Levobupivacaine upregulated the expression of miR-489-3p, which targets the cystine/glutamate transporter gene SLC7A11 and subsequently induces ferroptosis[107]. Ferroptosis is a type of cell death induced by iron-dependent lipid peroxidation that has been linked to the development of GC, possibly through changes in iron metabolism related to H. pylori infection[108]. However, the induction of ferroptosis is also a feasible strategy for treating different types of cancers. Several compounds are being tested[109].

Paroxetine is another SSRI-type antidepressant that has been shown to have anticancer effects through various processes including the induction of cell death or the arrest of cell proliferation. The mechanism of action in GC involves inhibition of the expression of DNA repair proteins, which leads to DNA damage and the activation of apoptosis. Paroxetine was also shown to inhibit cell viability in AGS and MKN-45 cell lines but had a much stronger effect on AGS[110]. Moreover, in some types of cancers, paroxetine can also act as a JAK inhibitor[111].

Risperidone is an antipsychotic drug, and its effects on cancer are contradictory. Studies have reported that risperidone increases the risk of some cancers, and other studies have indicated a negative correlation with other types of cancer. Recently, risperidone was found to have anticancer effects on the GC cell line KATO-III, and it produced apoptosis and inhibited growth in xenograft tumor mouse models. In addition, a population-based study revealed a correlation between risperidone use and decreased GC risk. However, the mechanism of action of risperidone remains poorly understood; inhibition of histone deacetylation, modulation of the dopamine receptor pathway, and disruption of cholesterol homeostasis have been proposed as mechanisms[112].

CONCLUSION

GC is a worldwide challenge, and the discovery of new treatments may lead to more favorable outcomes for patients. In this context, drug repurposing has emerged as a promising strategy because of its lower costs and fewer challenges for drug implementation. In most cases, the development of GC starts with H. pylori-induced gastritis and then progresses through a series of steps leading to the development of gastric adenocarcinoma. The progression through these steps is controlled by several pathways, some of which are also involved in GC. Therefore, drugs targeting these pathways could be effective against GC and also against its precursor lesions. This could lead to new treatment approaches that target GC development from an early stage, reducing its global burden. However, the scarcity of research on premalignant lesions makes it difficult to pinpoint the exact stage at which a compound could be effective. Moreover, a lack of studies on most drugs in preneoplastic lesion models, such as patient-derived organoids or primary cell culture, means that there is still a long way before repurposed drugs can be implemented in the clinic for the prevention of GC development. Patient-derived organoid models could be especially advantageous for research on these types of lesions, as they allow the different stages of precancerous lesions and GC to be recreated. Among the candidate compounds for drug repurposing in GC, several target molecular pathways involved in processes such as cell proliferation, invasion, or migration, and have the potential to eliminate tumor cells or reduce their growth. Some relevant pathways in GC include the MAPK, PI3K/AKT/mTOR, p53, JAK2/STAT3, HIF-1α, Wnt/β-catenin, NF-κB, and Hippo pathways. Although the PI3K/AKT/mTOR pathway is the target of most repurposed drugs presented in this review, some drugs act on more than one pathway. A better understanding of drug mechanisms of action and their target pathways could enable the development of new synergistic combinations. This would enhance the efficacy of chemotherapy and potentially reduce the required dose for individual drugs, thereby minimizing side effects. Another area that could be potentially beneficial to explore in the future includes repurposed immunotherapeutic drugs. Research on this topic is lacking for GC, but it could represent a promising approach for future studies.