Targetable pathways for drug repurposing in gastric cancer

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.