Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

Abstract

Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for. Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy, with potentially lower overall costs and shorter timelines. Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers, with the aid of some new emerging technologies, such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing. Therefore, in this review, we focus on summarizing the therapeutic potential of non-oncology drugs, including cardiovascular drugs, microbiological drugs, small-molecule antibiotics, anti-viral drugs, anti-inflammatory drugs, anti-neurodegenerative drugs, antipsychotic drugs, antidepressants, and other drugs in human cancers. We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies. Taken together, these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.

Graphical abstract

Repurposing non-oncology drugs have been used to improve cancer therapy with the processes of target identification, in vitro and in vivo experiments, and clinical trials from the current situation to future directions.

1. Introduction

Cancer is a major factor affecting global health and is now the second leading cause of death worldwide¹. According to the global cancer statistics, there were an estimated 19.3 million new emerging cancer cases and almost 10.0 million cancer deaths occurred in 2020². With such high cancer-associated morbidity and mortality, more attention should be paid to the discovery of innovative treatments and effective drugs. Traditionally, discovery of de novo antitumor drugs involves extensive pre-clinical and clinical studies to determine the safety and efficacy of the drug. Thus, the median cost of cancer drug development was $648.0 million (range $157.3 million to $1950.8 million) and the average time was 10–17 years³. Despite such investment, less than 1% of compounds are expected to enter clinical trials, let alone eventually come to market⁴. Thus, there is an urgent need to promote the drug development process for cancer treatment.

Drug repurposing (also called drug repositioning, reprofiling or redirecting), which applies an ‘old’ drug or drugs with structural modification to a new indication, has emerged as an alternative strategy for the development of antitumor drugs. Compared with de novo drug creation, there is already a great of well-defined data in terms of safety, toxicity, and pharmacological properties of repurposed drugs⁵. Thus, they can quickly pass preclinical and phase I clinical trials and transition rapidly to phase II and III clinical studies, and have higher probability of passing the clinical trial stage. Therefore, the time lag of research and development cycle can be reduced by 3–5 years and the costs by $0.3 billion^5,6. Considering these advantages, drug repurposing could be an innovative strategy to identify effective agents for cancer treatment (Fig. 1A).

Figure 1.

(A) The estimated time and main steps in traditional drug discovery and drug repurposing for cancer therapy. Traditional drug discovery for cancer therapy takes 10–17 years and drug repurposing takes only 3–12 years as it bypasses discovery of lead compound. (B) Main approaches of drug repurposing. There are mainly computational approaches including molecular docking, genetic association, pathway mapping, data mining, and signature matching as well as experimental approaches including phenotypic screening and binding assays for drug repurposing.

There are several successful cases of non-oncology drug repurposing for cancer therapy. For example, arsenic trioxide, a highly toxic substance that can be used for external skin erosion to remove decay, was first used to treat leukemia in 1972⁷. Now arsenic trioxide injection combined with tretinoin has been approved by the FDA as a first-line treatment for acute promyelocytic leukemia (APL)⁸. Thalidomide, a classic case of repurposing a drug, was used for treating morning sickness during pregnancy but eventually withdrawn from the market because of its teratogenicity. Now, it is repurposed for refractory multiple myeloma excluding in pregnant women⁹. Recently, metformin, a classic anti-diabetic II drug, is being intensively studied for its effects on many different cancers including prostate¹⁰, pancreatic¹¹, breast, ovarian and endometrial cancer¹². These drugs represent good demonstrations of non-oncology drug repurposing for cancer therapy and show that drug repurposing might be a way to develop new antitumor drugs.

2. New emerging technologies for drug repurposing

Given the increase of drug repurposing, several new technologies, especially bioinformatics and computer technology, have emerged and greatly improved the process of drug repurposing research. As we all know, the first step of drug repurposing strategy is to find effective targets of disease, and select compounds from the Drug Repurposing Hub (an interactive drug repurposing database which contains a comprehensive library of drugs that have reached the clinic, www.broadinstitute.org/repurposing) by certain methods¹³. Usually, the cancer genome database and other databases can be used to retrieve and screen the gene expression profile of the disease and proceed the enriched and the pathway analysis for differentially expressed genes to find their regulatory targets. Then, the optimal candidate compounds were calculated by Connectivity Map (CMap) ligatogram from numerous drug databases, such as PubChem, PharmGKB and DrugBank. Then, a pathway analysis and molecular docking can be conducted to evaluate the molecular mechanism of the candidate drug. Finally, the experiments in vitro and in vivo models are needed to validate their effects on new disease. With all these processes are finished, the drugs can carry out clinical trials to validate their pharmaceutical effects in human bodies¹⁴. At present, approaches to drug repurposing are mainly either computational approaches or experimental approaches, both of which are increasingly being used simultaneously in most situations to improve the efficiency of repurposing drug research. Computational approaches like signature matching, molecular docking, genetic association, pathway mapping and data mining are helping to find new targets of the drug by exploit known targets, drugs, disease biomarkers or pathways. They involve systematic analysis of big data (such as gene expression, chemical structure, genotype, or proteomic data) to match new indications of old drugs. For example, signature matching is based on the comparison of characteristics of one drug with those of another drug, disease, or clinical phenotype for its transcriptomic, structural, or adverse effect profiles to identify the same mechanism to treat other disease. It contains drug–disease and drug–drug similarity approaches for the same chemical structures expressing similar biological activity. Molecular docking can predict binding site complementarity between the ligand and the target, and this is an inexpensive, simple, and efficient way to find target drugs by high throughput screening. It may be interrogated against a particular target by drug libraries or drug libraries can be explored against an array of target receptors. For instance, mebendazole, an anti-parasitic drug, has potential to inhibit vascular endothelial growth factor receptor 2 (VEGFR2) by using high-throughput computational docking through molecular fit computations on plenty of FDA-approved drugs and protein structures. Another one is genetic association approaches to identify genes that are associated with a disease, and find potential drug targets of the disease. For instance, genome-wide association studies (GWAS) devote to identify genetic variants associated with common diseases and help identify novel targets for repurposing drug. However, these genes may not be ideal druggable targets. Therefore, pathway mapping could use upstream or downstream genetic, protein or disease data for identifying repurposing targets, and thus greatly improve the identification of drug targets. Recently, a technique termed network-wide association study (NetWAS) can identify disease gene associations much more accurately than GWAS and find more effective targets of anti-hypertensive drugs. To validate the effect of the old drug on cancer, a series of experiments need to be carried out to confirm their therapeutic effects in cancer. Therefore, experimental approaches, such as binding assays and phenotypic screening are indispensable, and can help to identify relevant target interactions in drug repurposing and to identify lead compounds from large compound libraries¹⁵. Binding assays can identify target interactions by interaction of ligand and receptor. For example, the cellular thermostability assay (CETSA) technique has been introduced as a way of mapping target engagement in cells using biophysical principles that predict thermal stabilization of target proteins. Phenotypic screening is to identify compounds that show disease-relevant effects in model systems without prior knowledge of the target affected. Typically, in vitro phenotypic screening can be carried out by a wide range of cell-based assays in a 96-well format. In the context of drug repurposing, it will screen numerous drugs in several cell lines. For instance, disulfiram, a drug used for alcohol abuse, is identified as a selective antineoplastic agent by high-throughput cell-based screening. With the assistance of these approaches, drug repurposing processes will improve greatly (Fig. 1B). Currently, there are many non-oncology drugs approved by FDA or in clinical trials including cardiovascular drug, antibiotics, antivirals, anti-inflammatory drugs, antipsychotics, and other non-oncology drugs which could be promising candidates for drug repurposing for cancer¹⁶. In this review, we focus on summarizing several repurposing non-oncology small-molecule drugs, as well as highlight their potential targets and molecular mechanisms in cancer therapy.

3. Molecular mechanisms repurposing non-oncology drugs in cancer therapy

There are several resources useful for screening non-oncology drug repurposing for cancer therapy. First, drugs that have been withdrawn due to cell toxicity when used for the given indication, but potentially exerting anticancer effects at lower doses. Second, drugs which are already on the market, especially the classic old drugs mentioned above that are used for drug repurposing. Because these drugs have been used in patients for many years, numerous new techniques could be used to find relationships between their original indications and cancer, and finally to identify antitumor effects of these drugs. In addition, compounds which have failed to pass the clinical trial phase could be restudied for their antitumor effects (Fig. 2). All these compounds might acquire or enhance their antitumor effects by structural modification, after which they can go to market for a new indication. All the above approaches provide abundant resources for discovering new anticancer drugs. Repurposing old drugs for antitumor therapy is an effective and economical way to develop new anticancer drugs. According to their original indications, we summarized these repurposing non-oncology small-molecule drugs for cancer therapy (Table 117, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114).

Figure 2.

The relevant signaling pathways of repurposing drugs in cancer therapy. The first one is JAK/STAT3 pathway for chloroquine, artemisinin, daraprim, benztropine and auranofin; RAS/RAF/ERK pathway for Digoxin, simvastatin, mevastatin, fluvastatin, nelfinavir, mebendazole, niclosamide; PI3K/AKT/mTOR pathway for prazosin, chloroquine, artemisinin, itraconazole, AM404, albendazole, ritonavir; and WNT/β-catenin pathways for asprine, benztropine, mebendazole, niclosamide.

Table 1.

Repurposing non-oncology small-molecule drugs for cancer therapy.

Original indication	Name	Cancer type	Mechanism	Ref.
Cardiovascular drugs	Losartan	Glioblastoma/Ovarian cancer	Decompressing vessels by reducing solid stress/reducing cell proliferation and growth/apoptosis	17,18
	Irbesartan	Prostate cancer	Targeting the proinflammatory cytokines, oxidative stress, apoptosis and TGF-β1/STAT-3 signaling	19
	Valsartan	Gastric cancer/Hepatic cancer	Targeting PI3K/AKT signaling	19
	Telmisartan	Lung cancer/Gastric cancer	WNT/β-catenin pathway	20
	Olmesartan	Breast cancer	Blocking RAS and NF-κB pathway leading to cytotoxicity and apoptosis	20
	Captopril	Colorectal cancer/Glioblastoma	Inhibiting angiogenesis and tumor invasion	21
	Enalapril	Colorectal cancer/Pancreatic cancer	Suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins	22,23
	Verapamil	Colorectal cancer/Breast cancer/Liver cancer	P-gp inhibitor	24
	Benazepril	Esophageal carcinoma/Gastrointestinal cancers	Inhibiting the cell growth	25
	Carvedilol	Glioblastoma/Pancreatic cancer/Breast cancer	Inducing mitochondrial damage/inhibiting cell proliferation and migration	26,27
	Propranolol	Hemangioma/Melanoma/Prostate cancer	Inhibiting angiogenesis and migration of cancer cells/interfering SOX18 transcriptional activity	28,29
	Atenolol	Gastric cancer	Inhibiting apoptosis, proliferation, migration and inflammatory cell responses for cancer therapy	30
	Digoxin	Pulmonary tumor/Prostate cancer/Breast cancer/Glioblastoma/Leukemia	Inhibiting Na+/K+ ATPase/apoptosis/suppressing HIF-1α accumulation/reducing ERK pathway/inducing expression of P21Cip1	31, 32, 33, 34
	Pitavastatin	Glioblastoma	Inhibiting mevalonate pathway/suppressing tumor cell MDR-1 protein and cell proliferation	35,36
	Simvastatin	Glioblastoma	Inhibiting cell proliferation and migration/apoptosis via increasing caspase-3 activity/downregulating the PI3K/AKT pathway	36
	Mevastatin	Glioblastoma	Inhibiting cell proliferation/apoptosis via suppressing RAS/ERK and PI3K/AKT pathways	37
	Fluvastatin	Breast cancer/Renal cancer	mTOR pathway/P21	38
	Atorvastatin	Glioblastoma	Inhibiting proliferation, migration and invasion/downregulating MMP via P38 MAPK pathway/apoptosis via caspase-8 and caspase-3 pathway	39
	Lovastatin	Glioblastoma	Inhibiting cell proliferation and MAPK pathway to induce apoptosis/increasing G0/G1 cell arrest	40
	Cerivastatin	Glioblastoma	Downregulating FAK phosphorylation to inhibit cell adhesion and invasion	39
	Ticlopidine	Glioblastoma	Autophagy	41
	Prazosin	Glioblastoma	Apoptosis via activating caspase-3	42
	Fenofibrate	Colon cancer	PPAR-α	43
	Verapamil	Glioblastoma	Inducing apoptosis by increasing the BAX/BCL-2 ratio	42
	Sildenafil	Glioblastoma	Increasing BBTB permeability via cGMP pathway	43
Microbiological agents	Chloroquine	Glioblastoma/Pancreatic cancer	Autophagy/inhibiting MMP-2 activity, cell proliferation and invasion	44
	Hydroxychloroquine	Cancer	Autophagy	44
	Mefloquine	Glioblastoma	Inhibiting cell proliferation via inducing cell cycle arrest in G2/M phase/autophagy	44
	Artemisinin	Breast cancer	Caspase-dependent apoptosis/STAT3	45,46
	Dihydroartemisinin	Cancer	Inducing oxidative stress response by reactive oxygen species and nitric oxide, DNA damage	45,46
	Artesunate	Cancer	Inhibiting angiogenesis and tumor-related signal transduction pathways	45,46
	Artemether	Cancer	Apoptosis, autophagy and ferroptosis	45,46
	Arteether	Cancer	Targeting NF-κB, MYC/MAX, AP-1, CREBP	45,46
	Daraprim	Triple-negative breast cancer	STAT3 inhibitor	47
	Quinacrine	Glioblastoma	Apoptosis and autophagy	48
	Amodiaquine	Melanoma	Apoptosis and autophagy	49
	Artefenomel	Cancer	Regulating the PD-L1 to PD-1 axis for establishing CD4+ T cell immunity	50
	Itraconazole	Prostate cancer/Glioblastoma/Non-small cell lung cancer/Liver cancer/Gastric cancer	Inhibiting hedgehog pathway, AKT–mTOR pathway and angiogenesis	51,52
	Posaconazole	Acute myeloid leukemia/Glioblastoma cancer	Targeting HK2-expressing	53
	Ketoconazole	Glioblastoma/Colorectal cancer	Reducing glycolytic metabolism	54
	Tioconazole	Breast cancer	Inhibiting ATG4 to suppress autophagy	55
	Enilconazole	Colorectal cancer	Inhibiting WNT/β-catenin and PI3K/AKT pathways	56
	Ciprofloxacin	Colon cancer	Inhibiting the ABCB1 efflux function to reverse MDR	57,58
Antibiotics	Bedaquiline	Triple-negative breast cancer	Leading mitochondrial dysfunction and ATP depletion	59, 60, 61
	Doxycycline	Breast cancer	Inhibiting the cancer stem cell phenotype and epithelial-to-mesenchymal transition	62
	Tigecycline	Ovarian cancer/Myeloid leukemia	Targeting MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic P21CIP1/Waf1, and WNT/β-catenin signaling	62
	Clofoctol	Prostate cancer	Inhibiting cancer cell growth through activating ER stress and three branches of the UPR pathway	63
Anti-viral drugs	Ritonavir	Ovarian cancer/Melanoma	Blocking AKT/mTOR pathway/expressing G1 phase	64
	Nelfinavir	Melanoma/Rectal cancer	Suppressing PAX3 and MITF expression	65,66
	Maraviroc	Triple-negative breast cancer	Blocking lymphangiogenesis and cancer metastasis	67,68
	L-870810	Cancer	Cytotoxicity in cancer cell and inhibiting select oncogenic kinases	69
Anti-inflammatory drugs	Aspirin	Colon cancer/Breast cancer	Inhibiting COX enzymes/downregulating WNT/β-catenin pathway	70,71
	Auranofin	Glioblastoma	Inducing cell ferroptosis	72
	Celecoxib	Glioblastoma/Lung cancer	P53-dependent G1 cell cycle arrest and autophagy/downregulating NF-κB, caspase-9, BAX and BCL-XL	73,74
	Ibuprofen	Prostate cancer/Melanoma/Lung cancer/Adenocarcinoma/Gastric cancer	Inhibiting COX enzymes/reducing angiogenesis and cell proliferation/apoptosis	75
Anti-neurodegenerative drugs	Benztropine	Breast cancer/Pancreatic cancer	Acting on SLC6A3/DAT and STAT3 pathways	76
	Benserazide	Colon cancer/Melanoma	Inhibiting HK2 pathway	77
	Donepezil	Glioblastoma	Increasing cell mitosis duration and inducing cell mitotic arrest	78
	Memantine	Glioblastoma	Inhibiting proliferation/autophagy	79
	Riluzole	Hepatocellular carcinoma	Inducing caspase-dependent apoptosis and G2/M cell cycle arrest	80
Antipsychotic drugs	Chlorpromazine	Glioblastoma/Colorectal cancer	Inhibiting AKT/mTOR pathway	81
	Fluphenazine	Triple-negative breast cancer	Inducing G0/G1 cell cycle arrest/apoptosis	82
	Penfluridol	Glioblastoma/Triple-negative breast cancer	Inhibiting transcription factor GLI1 and integrin pathway	83
	Olanzapine	Glioblastoma	Inhibiting proliferation, migration and anchorage-independent growth/inducing apoptosis, necrosis and cytostasis	84
	Risperidone	Adenocarcinoma	Decreasing proliferation	85
	Clomipramine	Glioblastoma	Activating JNK/JUN pathway/increasing cytochrome c release and apoptosis activated by caspase-3	86
	KRICT-9	Cancer	Inhibiting STAT3	47
Antidepressants	Imipramine	Glioblastoma/Small cell lung cancer	Inducing high level of autophagy and cell death	87
	Trimipramine	Prostate cancer	Increasing plasma levels of CYP2D6 substrates	88
	Amitriptyline	Prostate cancer	Increasing plasma levels of CYP2D6 substrates	88
	All-trans retinoic acid (ATRA)	Colorectal cancer/Acute myeloid leukemia	Enhancing the effects of EVI1	89
	Tranylcypromine	Breast cancer	LSD1/HDACs dual inhibitor	90
	Fluoxetine	Hepatocellular cancer/Lung cancer	Blocking AKT/NF-κB or ERK/NF-κB activation and inducing apoptosis	91
	Citalopram	Burkitt lymphoma	Inhibiting proliferation/inducing apoptosis in cancer cell/downregulating AKT pathway	92
	Paroxetine	Breast cancer	Inducing apoptosis through Ca2+ and P38 MAP kinase-dependent ROS generation	93
	Sertraline	Liver cancer/Breast cancer/Prostate cancer	Dual activation of apoptosis and autophagy signaling by deregulating redox balance	94
	Proscillaridin A	Glioblastoma	Activating GSK3β/alternating microtubule dynamics	95
	Valproic acid	Prostate cancer/Gastric cancer	Inhibiting histone deacetylase to reduce cancer cell proliferation/apoptosis/inhibiting angiogenesis	96
Other drugs	Metformin	Glioblastoma/Non-small cell lung cancer/Rectal cancer/Prostate cancer/Ovarian cancer	Autophagy/apoptosis/inducing G1 cell arrest	97
	Pioglitazone	Lung cancer/Glioblastoma	PPARγ/inhibiting WNT/β-catenin pathway/apoptosis	98,99
	Repaglinide	Glioblastoma	Inhibiting proliferation and migration of tumor cell/reducing BCL-2, Beclin1 and PD-L1 expression/blocking immune checkpoint signaling	95
	Rosiglitazone	Glioblastoma	Inhibiting cell proliferation by causing G2/M arrest and apoptosis	100
	Buformin	Breast cancer	Inhibiting receptor tyrosine kinase (RTK) and mTOR pathway/reducing cell proliferation	97
	Ciglitazone	Glioblastoma	Lossing mitochondrial membrane potential along with increasing ROS	98
	Phenformin	Breast cancer/Rectal cancer	Targeting signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling	101
	Mebendazole	Glioblastoma	Inhibiting proliferation and angiogenesis/BRAF–MEK–ERK pathway/upregulating expression of pro-inflammatory genes	102
	Albendazole	Lung cancer	Inhibiting HIF-1α-dependent glycolysis and VEGF	103
	Flubendazole	Breast cancer	Inhibiting STAT3 and activating autophagy/targeting P53 and promoting ferroptosis	104
	Niclosamide	Hepatocellular carcinoma/Adrenocortical carcinoma/Leukemia/Lung cancer/Osteosarcoma	Reversing cancer gene expression/inhibiting tumor cell proliferation	105, 106, 107
	Disulfiram	Glioblastoma	Activating JNK and P38 pathways/inhibiting NF-κB and MGMT/inducing ROS/DNA damage	108
	AM404	Colorectal cancer/Glioblastoma	Induce cell differentiation and impede neoplastic cell growth/suppressing the oncogenic FBXL5	109
	Salbutamol	Breast cancer	Inhibiting migration, invasion and metastasis	110
	Raloxifene	Breast cancer	Inhibiting IL-6/GP130 interaction	111
	Bazedoxifene	Breast cancer	Inhibiting cell viability, cell migration, colony formation, and tumor growth and inducing apoptosis	112
	Thiabendazole	Prostate cancer/Breast cancer	Cytotoxicity	113
	Azelnidipine	Cancer	Blocking CD47/SIRPα and TIGIT/PVR pathways through co-targeting SIRPα and PVR	114

3.1. Cardiovascular drugs repurposing for cancer therapy

Several experimental studies have demonstrated that drugs approved by FDA, which are commonly prescribed for the treatment or prevention of cardiovascular diseases, have promising anticancer properties¹¹⁵. Some analyses of retrospective clinical data suggest that the use of cardiovascular drugs to treat hypertension in cancer patients is likely to extend survival of patients with pancreatic and other cancers. Some of these drugs have advanced to randomized clinical trials (RCTs) to confirm their antitumor effects (Table 2, sourced by http://clinicaltrials.gov). For example, losartan (Fig. 3, 1) is a cardiovascular agent affecting the renin-angiotensin system (RAS), which is also a potential target for modulating tumor-infiltrating immune cells. In tumors, it could act on RAS to decompress vessels by reducing solid stress to improve vessel density and decrease vessel diameter and eventually normalize the tumor microenvironment¹⁷. Subsequently, it was found that losartan depletes the matrix via inducing antifibrotic miRNAs including miR-133 and miR-29, which can reduce collagen I levels in cancer cells to modulate solid stress^17,18. Additionally, losartan reduced cell proliferation and tumor growth as well as inducing apoptosis. In a phase II clinical trial of losartan, patients with previously untreated unresectable pancreatic tumor showed downstaging of locally advanced pancreatic ductal adenocarcinoma and a higher success rate on subsequent surgical resection¹¹⁶. This suggests that losartan may be worth studying as a drug active for pancreatic cancer. Similarly, irbesartan (Fig. 3, 2), valsartan (Fig. 3, 3), telmisartan (Fig. 3, 4) and olmesartan (Fig. 3, 5) also mediate anticancer effects via a mechanism like that of lorsartan^19,20. Captopril (Fig. 3, 6) also exerts effect on RAS and shows efficacy for inhibiting colorectal liver metastases by significantly decreasing tumor viability and impairing metastatic growth. It modulates the spatial and temporal infiltration of CD3⁺ CD4⁺ lymphocytes into the tumor, and the activation of T cell subtypes in the tumor and liver tissues²¹. Enalapril (Fig. 3, 7), verapamil (Fig. 3, 8) and benazepril (Fig. 3, 9) are also reported to show effects on cancer22, 23, 24, 25.

Table 2.

Repurposing non-oncology drugs under clinical trials.

Drug name	Cancer type	Clinical trial identifier
Losartan	Pancreatic cancer	NCT03563248 (phase 2)
	Pancreatic cancer	NCT01821729 (phase 2)
	Pancreatic cancer	NCT04106856 (phase 1)
	Osteosarcoma	NCT03900793 (phase 1)
	Glioblastoma	NCT03951142 (phase 2)
Captopril	Lung cancer	NCT00077064 (phase 2)
	Infantile hemangioma	NCT04288700 (phase 4)
Verapamil	Brain cancer	NCT00706810 (phase 2)
	Hodgkin lymphoma	NCT03013933 (phase 1)
Carvedilol	Breast cancer	NCT02993198 (phase 2)
	Glioblastoma	NCT03980249 (early phase 1)
	Glioblastoma	NCT03861598 (early phase 1)
Propranolol	Gastric cancer	NCT04005365 (phase 2)
	Breast cancer	NCT02596867 (phase 2)
	Bladder cancer	NCT04493489 (phase 2)
	Pancreatic neoplasms	NCT03838029 (phase 2)
	Breast cancer	NCT02596867 (phase 2)
	Breast cancer	NCT02013492 (early phase 1)
	Prostate carcinoma	NCT03152786 (phase 2)
	Skin melanoma	NCT01988831 (phase 2)
	Esophageal adenocarcinoma	NCT04682158 (phase 2)
	Infantile hemangioma	NCT01056341 (phase 2/3)
	Cavernous malformations	NCT03523650 (phase 1)
Atenolol	Hemangioma	NCT02342275 (phase 3)
	Infantile hemangioma	NCT03237637 (phase 3)
Digoxin	Head and neck cancer	NCT02906800 (phase 1/2)
	Prostate cancer	NCT01162135 (phase 2)
	Malignant melanoma	NCT01765569 (phase 1)
	Melanoma	NCT02138292 (phase 1)
Pitavastatin	Breast cancer	NCT04705909 (phase 2/3)
	Acute myeloid leukemia	NCT04512105 (phase 1)
Simvastatin	Breast cancer	NCT03324425 (phase 2)
	Breast cancer	NCT00334542 (phase 2)
	Pancreatic cancer	NCT00944463 (phase 2)
	Breast cancer	NCT00807950 (phase 2)
	Colorectal cancer	NCT01110785 (phase 2)
	Adenocarcinoma of rectum	NCT02161822 (phase 2)
	Colorectal cancer	NCT00313859 (phase 2)
	Myeloma	NCT01332617 (phase 2)
	Multiple myeloma	NCT00281476 (phase 1/2)
	Chronic lymphocytic leukemia	NCT00828282 (phase 1)
Atorvastatin	Prostate cancer	NCT04026230 (phase 3)
	Prostatic neoplasms	NCT01821404 (phase 2)
	Endometrial cancer	NCT02767362 (early phase 1)
	Malignant disease	NCT03560882 (phase 1)
	Kidney cancer	NCT00490698 (phase 2)
	Acute myelogenous leukemia	NCT01491958 (phase 2)
	Myeloma	NCT00164086 (phase 1)
	Glioblastoma multiforme	NCT02029573 (phase 2)
	Hepatocellular carcinoma	NCT02819869 (phase 2)
Lovastatin	Breast cancer	NCT00584012 (phase 1)
	Ovarian cancer	NCT00585052 (phase 2)
	Breast cancer	NCT00285857 (phase 2)
	Acute myeloid leukemia	NCT00583102 (phase 1/2)
	Melanoma	NCT00963664 (phase 2)
	Melanoma	NCT00462280 (phase 2)
	Neurofibromatosis type 1	NCT00853580 (phase 2)
Verapamil	Brain cancer	NCT00706810 (phase 2)
	Recurrent hodgkin lymphoma	NCT03013933 (phase 1)
Sildenafil	Pancreatic cancer	NCT02106871 (phase 1)
	Lung cancer	NCT00752115 (phase 2/3)
	Solid tumor	NCT02466802 (phase 1)
	Lymphatic malformations	NCT02335242 (phase 2)
	Glioblastoma	NCT01817751 (phase 2)
	Lymphangioma	NCT01290484 (phase 1/2)
	Waldenstrom's macroglobulinemia	NCT00165295 (phase 2)
Chloroquine	Lung cancer	NCT01575782 (phase 1)
	Breast cancer	NCT02333890 (phase 2)
	Lung cancer	NCT00969306 (phase 1)
	Breast cancer	NCT01446016 (phase 2)
	Malignant neoplasm	NCT02071537 (phase 1)
	Carcinoma	NCT01023477 (phase 1/2)
	Glioma	NCT02496741 (phase 1/2)
	Brain metastasis	NCT01894633 (phase 2)
	Glioblastoma multiforme	NCT02378532 (phase 1)
	Glioblastoma	NCT02432417 (phase 2)
	Glioblastoma	NCT04772846 (phase 1/2)
	Glioblastoma multiforme	NCT00224978 (phase 3)
Artemisinin	Ovarian cancer	NCT04805333 (phase 1)
Quinacrine	Prostatic cancer	NCT00417274 (phase 2)
	Lung cancer	NCT01839955 (phase 1)
	Colorectal adenocarcinoma	NCT01844076 (phase 1/2)
	Renal cell carcinoma	NCT00574483 (phase 2)
Itraconazole	Prostate cancer	NCT03513211 (phase 1/2)
	Prostate cancer	NCT00887458 (phase 2)
	Prostate cancer	NCT02054793 (phase 1/2)
	Lung cancer	NCT03664115 (phase 2)
	Esophageal cancer	NCT02749513 (early phase 1)
	Lung cancer	NCT02357836 (early phase 1)
	Ovarian cancer	NCT03081702 (phase 1/2)
	Lung cancer	NCT00769600 (phase 2)
	Lung cancer	NCT02157883 (phase 1)
	Solid tumours	NCT01900028 (phase 1)
	Prostate cancer	NCT01450683 (phase 2)
	Lung cancer	NCT01752023 (phase 2)
	Esophageal neoplasm	NCT04481100 (phase 2)
	Prostate adenocarcinoma	NCT01787331 (phase 2)
	Advanced solid tumors	NCT02259010 (phase 1)
Ketoconazole	Prostate cancer	NCT00895310 (phase 2)
	Breast cancer	NCT00212095 (phase 2)
	Prostate cancer	NCT01036594 (phase 2)
	Prostate cancer	NCT00953576 (phase 1/2)
	Prostate cancer	NCT00003084 (phase 2)
	Granulosa cell tumour of the ovary	NCT01584297 (phase 2)
	Advanced cancer	NCT00708591 (phase 1)
	Prostatic neoplasms	NCT00032825 (phase 1)
	Breast cancer	NCT03796273 (early phase 1)
	Solid tumors	NCT00697437 (phase 2)
Ciprofloxacin	Prostate cancer	NCT02252978 (phase 2)
	Bladder cancer	NCT00003824 (phase 3)
	Leukemia	NCT02773732 (phase 1/2)
	Pancreatic ductal adenocarcinoma	NCT04523987 (phase 1)
Doxycycline	Pancreatic cancer	NCT02775695 (phase 2)
	Breast carcinoma	NCT02874430 (phase 2)
	Breast cancer	NCT01847976 (phase 2)
	Head and neck squamous cell carcinoma	NCT03076281 (phase 2)
	Lymphangioleiomyomatosis	NCT00989742 (phase 4)
	Cutaneous T-cell lymphoma	NCT02341209 (phase 2)
	Melanoma	NCT01590082 (phase 1/2)
Ritonavir	Breast cancer	NCT01009437 (phase 1)
Nelfinavir	Non-hodgkin lymphoma/Hodgkin lymphoma/Gastric cancer/Nasopharyngeal cancer	NCT02080416 (early phase 1)
	Colorectal cancer	NCT00704600 (phase 1/2)
	Head and neck neoplasms	NCT01065844 (phase 2)
	Non-small cell lung cancer	NCT00791336 (phase 2)
	Non-small cell lung cancer	NCT01108666 (phase 2)
	Glioblastoma	NCT00694837 (phase 1)
	Glioma	NCT01020292 (phase 1)
Maraviroc	Hematologic malignancy	NCT01785810 (phase 2)
	Metastatic colorectal cancer	NCT03274804 (phase 1)
Aspirin	Colorectal cancer	NCT00578721 (phase 2)
	Colorectal cancer	NCT02607072 (phase 3)
	Colorectal cancer	NCT00565708 (phase 3)
	Colorectal cancer	NCT02647099 (phase 3)
	Colorectal cancer	NCT02945033 (phase 3)
	Colorectal cancer	NCT03957902 (phase 2)
	Colorectal cancer	NCT00002527 (phase 3)
	Colorectal cancer	NCT02125409 (phase 3)
	Colorectal cancer	NCT02965703 (phase 2)
	Lynch syndrome	NCT02813824 (phase 3)
	Lynch syndrome I	NCT02497820 (phase 3)
	Colon cancer/Rectal cancer	NCT00468910 (phase 2)
	Colon cancer	NCT02467582 (phase 3)
	Colon cancer	NCT02301286 (phase 3)
	Colon cancer	NCT03464305 (phase 3)
	Colon cancer	NCT00224679 (phase 3)
	Rectal cancer	NCT03170115 (phase 2)
	Gastric cancer	NCT04214990 (phase 3)
	Breast cancer	NCT03491410 (phase 2/3)
	Breast cancer	NCT00727948 (early phase 1)
	Node positive HER2 negative breast cancer	NCT02927249 (phase 3)
	Fallopian tube cancer	NCT03771651 (early phase 1)
	Non-small cell lung cancer	NCT01058902 (phase 3)
	Non-small cell lung cancer	NCT01707823 (early phase 1)
	Prostate cancer/Gastro-oesophageal cancer/Colorectal cancer/Breast cancer	NCT02804815 (phase 3)
	Urinary bladder neoplasms	NCT02350543 (phase 4)
	Esophageal squamous cell carcinoma	NCT03900871 (early phase 1)
	Cutaneous melanoma	NCT03396952 (phase 2)
	Nasopharyngeal carcinoma	NCT03290820 (phase 2)
	Glioblastoma	NCT00790452 (phase 2)
	Melanoma	NCT04062032 (phase 2)
	Melanoma	NCT04066725 (phase 2)
Celecoxib	Endometrium cancer	NCT03896113 (phase 2)
	Breast cancer	NCT00328432 (phase 1)
	Breast cancer	NCT01695226 (phase 2)
	Breast cancer	NCT00056082 (phase 2)
	Breast cancer	NCT00045591 (phase 2)
	Breast cancer	NCT00291694 (phase 2)
	Breast cancer	NCT02429427 (phase 3)
	Metastatic cancer	NCT03864575 (phase 2)
	Oral squamous cell carcinoma	NCT02739204 (phase 2)
	Lung cancer	NCT00104767 (phase 1)
	Lung cancer	NCT01503385 (phase 2)
	Lung cancer	NCT00020878 (phase 2)
	Prostate cancer	NCT02840162 (phase 2)
	Prostate cancer	NCT00022399 (phase 2)
	Prostate cancer	NCT00073970 (phase 2)
	Prostate cancer	NCT00136487 (phase 2/3)
	Recurrent respiratory papillomatosis	NCT00571701 (phase 2)
	Cervix neoplasms	NCT00152828 (phase 1/2)
	Head and neck cancer/Lung cancer	NCT00527982 (phase 2)
	Non muscle invasive bladder cancer	NCT02343614 (phase 2)
	Head and neck cancer	NCT00061906 (phase 2)
	Head and neck cancer	NCT00014404 (phase 2)
	Smoldering multiple myeloma	NCT00099047 (phase 2)
	Recurrent bladder cancer	NCT00006124 (phase 2/3)
	Uterine cancer	NCT00231829 (phase 2)
	Colorectal carcinoma	NCT00582660 (phase 2)
	Cervical carcinoma	NCT00081263 (phase 2)
	Non-small cell lung cancer	NCT00108186 (phase 1)
	Lymphangioleiomyomatosis	NCT02484664 (phase 2)
Memantine	Glioblastoma	NCT01260467 (phase 2)
Chlorpromazine	Glioblastoma multiforme/MGMT-unmethylated glioblastoma	NCT04224441 (phase 2)
Fluphenazine	Multiple myeloma and plasma cell neoplasm	NCT00335647 (phase 1/2)
	Multiple myeloma	NCT00821301 (phase 1)
Imipramine	Breast cancer	NCT03122444 (early phase 1)
Metformin	Breast cancer	NCT01302002 (early phase 1)
	Breast cancer	NCT04387630 (phase 2/3)
	Breast cancer	NCT01266486 (phase 2)
	Breast cancer	NCT01310231 (phase 2)
	Breast cancer	NCT01589367 (phase 2)
	Breast cancer	NCT01566799 (phase 2)
	Breast cancer	NCT00930579 (phase 2)
	Breast cancer	NCT00909506 (phase 2)
	Prostate cancer	NCT03137186 (phase 2)
	Prostate cancer	NCT01620593 (phase 2)
	Prostate cancer	NCT01243385 (phase 2)
	Prostate cancer	NCT01215032 (phase 2)
	Prostate cancer	NCT01677897 (phase 2)
	Prostate cancer	NCT01733836 (phase 2)
	Prostate cancer	NCT04925063 (phase 2)
	Prostate cancer	NCT00881725 (phase 2)
	Prostate cancer	NCT01864096 (phase 3)
	Prostate cancer	NCT03031821 (phase 3)
	Endometrial cancer	NCT01205672 (early phase 1)
	Endometrial cancer	NCT01911247 (early phase 1)
	Endometrial cancer	NCT02990728 (phase 2)
	Endometrial cancer	NCT02042495 (phase 2)
	Endometrial cancer	NCT04792749 (phase 3)
	Colorectal cancer	NCT01632020 (phase 2)
	Colorectal cancer	NCT01926769 (phase 2)
	Colon cancer	NCT01440127 (phase 1)
	Rectal cancer	NCT02437656 (phase 2)
	Bladder cancer	NCT03379909 (phase 2)
	Head and neck cancer	NCT02402348 (early phase 1)
	Head and neck squamous cell cancer	NCT02083692 (early phase 1)
	Non-small cell lung cancer	NCT01997775 (phase 2)
	Non-small cell lung cancer/Lung cancer	NCT03086733 (phase 2)
	Non-small cell lung cancer/Lung cancer	NCT01717482 (phase 2)
	Well-differentiated neuroendocrine tumors	NCT02279758 (phase 2)
	Hepatocellular carcinoma	NCT02319200 (phase 3)
	Chronic lymphocytic leukemia	NCT01750567 (phase 2)
Pioglitazone	Lung cancer	NCT00780234 (phase 2)
	Thyroid cancer	NCT01655719 (phase 2)
	Non-small cell lung cancer	NCT00923949 (phase 2)
	Non-small cell lung cancer	NCT01342770 (phase 2)
	Pancreatic cancer	NCT01838317 (phase 2)
	Pancreatic cancer	NCT00867126 (early phase 1)
	Prostate cancer	NCT04658849 (early phase 1)
	Skin squamous cell cancer	NCT02347813 (phase 2)
Mebendazole	Medulloblastoma/Astrocytoma/Glioblastoma/Anaplastic astrocytoma/Brain stem neoplasms/Oligodendroblastoma/Anaplastic oligodendroglioma/Malignant glioma	NCT02644291 (phase 1)
	High-grade glioma	NCT01729260 (phase 1)
Niclosamide	Colon cancer	NCT02687009 (phase 1)
	Colorectal cancer	NCT02519582 (phase 2)
Disulfiram	Metastatic breast cancer	NCT03323346 (phase 2)
	Melanoma	NCT00256230 (phase 1/2)
Raloxifene	Endometrial cancer	NCT00004915 (phase 2)

Figure 3.

Chemical structures of 1–16 as cardiovascular drugs for repurposing in cancer therapy.

Another cardiovascular drug carvedilol (Fig. 3, 10) affects β-adrenoreceptor for treatment of hypertension, and its potential ability to resistance to skin cancer caused by sun exposure was serendipitously revealed as a result of an experimental error, a new finding first published in 2017^117,118. However, it is little known about how carvedilol affects cancer-related outcomes. To explain this, it was discovered that carvedilol blocks the effects of sympathetic nervous system activation through β-adrenoreceptor signaling and metastasis and invasion of breast cancer were blocked in a mouse model²⁶. Additionally, carvedilol induced mitochondrial damage including mitochondrial swelling, crista damage and formation of myelin figures, and inhibited growth factor receptors to mediate anti-proliferative and anti-migratory effects in cancer cells and increase survival in experimental animal models of pancreas cancer²⁷. In clinical trials, carvedilol is often combined with imatinib to enhance in vitro anticancer activity in glioma or with trastuzumab to prevent and alleviate drug-related cardiotoxicity in breast cancer^119,120. These results suggest that β-blockers could represent novel drugs to treat cancer progression. Propranolol (Fig. 3, 11) is a non-selective β-adrenoreceptor blocker used to treat arrhythmia, but it also exerts effect on melanoma by inhibiting angiogenesis and disrupting migration of cancer cells via inhibition of noradrenaline-dependent responses²⁸. Propranolol is the first line therapy for infantile hemangioma, acting by interference with SOX18 transcriptional activity to inhibit angiogenesis²⁹. Atenolol (Fig. 3, 12) acts in the same manner as propranolol to inhibit apoptosis, proliferation, migration, and inflammatory cell responses for cancer therapy³⁰. These drugs are new attractive, inexpensive, and relatively safe therapeutics for cancers¹²¹. Cardiac glycosides (CGs) such as digoxin (Fig. 3, 13) and digitoxin are compounds found in natural sources that are used to treat different cardiac conditions. The antitumor effects of CG were suggested in 1979 in a study of chemotherapy for breast cancer treated in combination with digitalis¹²². It was used to treat cardiovascular disease by inhibiting the Na⁺/K⁺-ATPase which results in an elevation of the intracellular Na⁺ level in cardiomyocytes, such that the Na⁺/Ca²⁺ exchanger mechanism is stimulated. This results in increased intracellular Ca²⁺ concentration, prompting myocardial contractibility^31,32. However, CGs can also bind to Na⁺/K⁺-ATPase in cancer cells and disrupt it, causing apoptosis¹¹⁵. In addition, CGs could treat cancer via other targets. The eukaryotic translation initiation factor 4F complex (eIF4F) which regulates the translational initiation has been recognized as a potential chemotherapeutic target in triple-negative breast cancer (TNBC). CGs could treat TNBC as an inhibitor of eIF4F which is modulated by c-MYC levels³². c-MYC can be phosphorylated through the RAS–ERK pathway, and CGs may also be related to the reduction of hypoxia-induced activation of the ERK pathway³³. CGs also induce the expression of P21Cip1, an inhibitor of cyclin-dependent kinases, resulting in growth arrest¹⁶. In addition, CGs can affect TRAIL-mediated apoptosis and suppress HIF-1a accumulation for cancer therapy³⁴. Therefore, CGs are a broad category of compounds derived from natural products which show potential anticancer effects by targeting multiple pathways¹²³. Statins are common cholesterol-lowering prescription drugs which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), a rate-limiting enzyme of the mevalonate pathway, thus decreasing cholesterol biosynthesis. Recently, it was discovered that the mevalonate pathway coincides with some cancer pathway, and thus, that cholesterol-lowering drugs may also be used in cancer therapy³⁵. For example, pitavastatin (Fig. 3, 14), which is the most promising of these for repurposing as an antitumor drug, can induce death in almost half of neoplastic cells but with much lower mortality in normal cells. Its antitumor mechanism is related to the mevalonate pathway and macropinocytosis. Mevalonate pathway provides geranylgeranyl pyrophosphate (GGPP) which cancer cells depend for macropinocytosis nutrient uptake. Statins selectively inhibit the mevalonate pathway, which eventually leads to amino acid starvation and subsequent cell death due to the depletion of GGPP³⁶. Pitavastatin also shows anticancer activity through inducing autophagic death by inhibiting NF-κB, suppressing tumor cell MDR-1 protein and inhibiting cell proliferation. In addition, other statins like simvastatin (Fig. 3, 15), mevastatin (Fig. 3, 16) and fluvastatin (Fig. 4, 17) can suppress the PI3K/AKT and RAS/ERK pathways to inhibit cancer^37,38,124. Atorvastatin (Fig. 4, 18) downregulates expression of membrane type 1 MMP via the P38 MAPK pathway³⁹. Lovastatin (Fig. 4, 19) may inhibit G0/G1 cell cycle transition to prevent cell proliferation and activate LKB1–AMPK–P38MAPK–P53–survivin cascade to cause MCF-7 cell death⁴⁰. Cerivastatin (Fig. 4, 20) downregulates FAK phosphorylation to inhibit cell adhesion and invasion^6,125. Statins were found to regulate cell proliferation, apoptosis, and tumor progression in cancer patients, and could reduce cancer induction and improve survival¹²⁶.

Figure 4.

Chemical structures of 17–25 as cardiovascular drugs for repurposing in cancer therapy.

In addition, ticlopidine (Fig. 4, 21) also shows antitumor efficacy via inducing cell autophagy by coordinately elevating the level of cAMP⁴¹. Prazosin (Fig. 4, 22) has been found to have off-target activity to inhibit glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway, which results in caspase-3 activation⁴². Fenofibrate (Fig. 4, 23) can be developed for chemoprevention or treatment of colon cancer by activating peroxisome proliferators-activated receptors-α (PPAR-α) which regulates the occurrence of colon cancer associated with DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of P27⁴³. Verapamil (Fig. 4, 24) and sildenafil (Fig. 4, 25) are also reported to effect on cancer^127,128.

These drugs were initially found to have antitumor effect via their original target, but some of them have multiple targets for cancer treatment. Therefore, other new targets are likely to be found by studying and seeking the repurposing of cardiovascular drugs. Thus, cardiovascular drugs represent a broad category of drugs for repurposing for cancer therapy by several pathways. The first step of drug repurposing is to find its effective target for cancer, whereby some drugs have the same antitumor target as in their original indications. In fact, the potential of cardiovascular drugs in oncology remains clinically untapped because most available clinical data originate from retrospective studies and small prospective studies that are potentially biased. Therefore, more effort could be exerted in this area of repurposing drugs for tumor treatment.

3.2. Microbiological agents repurposing for cancer therapy

Microbiological agents are mainly used for treating malaria, fungal and bacterial infections. Some of these drugs have shown promising anticancer activity and entered phase II/III clinical trials.

3.2.1. Anti-malaria drugs

Chloroquine (Fig. 5, 26) and its derivatives hydroxychloroquine (Fig. 5, 27) and mefloquine (Fig. 5, 28) are used for the prevention and treatment of malaria and have shown promising results in combination with other anticancer drugs. A key target is the inhibition of autophagy by preventing lysosomal acidification or lysosome fusion through targeting AMPK pathway. NF-κB and P53 also inhibit tumor cell proliferation and growth by autophagy in cancer cells⁴⁴. In a phase I/II trial of everolimus and hydroxychloroquine in patients, decreased cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor was observed¹²⁹. For autophagy in stromal cells, chloroquine or their derivatives could be promising antineoplastic agents in the next decades.

Figure 5.

Chemical structures of 26–37 as microbiological agents for repurposing in cancer therapy.

Artemisinin (Fig. 5, 29) and its derivatives dihydroartemisinin (Fig. 5, 30), artesunate (Fig. 5, 31), artemether (Fig. 5, 32), arteether (Fig. 5, 33) have also shown selective anticancer properties in phase I/II trials via their cytotoxic effects. It was found that artemisinin could induce caspase-dependent apoptosis by the intrinsic mitochondrial pathway, regulated by antiapoptotic proteins like BCL-2, and proapoptotic factors like BID and BAK in cancer cells⁴⁵. Additionally, artemisinin exhibits immunomodulation in cancer by inhibiting T-cell activation and proliferation and inhibiting signal transducer and activator of transcription (STAT3), cancer metabolism and cancer stem cells as a novel and promising approach to treat tumors⁴⁶. However, the use of artemisinin has unexpected resulted in hepatotoxicity, thus, its repurposing for cancer therapy must be approached with caution¹³⁰. Daraprim (Fig. 5, 34) is another anti-malaria drug which also targets STAT3 to treat cancer⁴⁷. Quinacrine (Fig. 5, 35) and amodiaquine (Fig. 5, 36) have been found to kill tumors by induction of apoptosis and autophagy^48,49. These drugs similarly target cell autophagy or apoptosis via several pathways to treat cancer. Some of these drugs like artemisinin, which is derived from the extracted ingredients of traditional Chinese medicine to treat malaria worldwide, show effects on cancer therapy. Artemisinin derivatives with structure modification could have enhanced anticancer effects. For example, one synthetic derivative, OZ439 (artefenomel) (Fig. 5, 37), shows effective and promising alternative cancer therapeutic effects by stabilizing the peroxide pharmacophore⁵⁰. Therefore, natural products of traditional Chinese medicine are also a new way to explore effective anticancer drugs.

3.2.2. Anti-fungal drugs

Some azole anti-fungal agents approved by the FDA also show antitumor effects, for example, itraconazole was recently identified as a promising anticancer chemotherapeutic through high-throughput screens. Itraconazole (Fig. 6, 38) exerts its antifungal effects through potent inhibition of CYP51, while its side chain region may inhibit the hedgehog (Hh) signaling pathway which is a signaling cascade responsible for cell proliferation, differentiation, and tissue growth in embryogenesis⁵¹. In addition, itraconazole can induce cholesterol redistribution to trigger autophagy via inhibition of the AKT-mTOR signaling pathway, finally inhibiting cell proliferation⁵². Posaconazole (Fig. 6, 39) is a derivative of itraconazole that exerts antitumor effects by targeting hexokinase2 (HK2) to regulate tumor growth, invasion, and angiogenesis⁵³. Ketoconazole (Fig. 6, 40) was the first oral active azole antifungal agent synthesized (in 1976) but it was withdrawn from the European market in 2013 because of its severe hepatotoxic adverse reactions. It also has anticancer effects by targeting the HK2 pathway and exacerbating mitophagy to induce apoptosis by downregulating cyclooxygenase-2 (COX2) in hepatocellular carcinoma⁵⁴. Tioconazole (Fig. 6, 41) shows anticancer effect by enhancing chemotherapeutic drug-induced cytotoxicity in cancer cells and suppressing autophagy by inhibiting ATG4 to regulate tumor growth, metastasis and resistance to chemotherapy and sensitize cancer cells to chemotherapy⁵⁵. Enilconazole (Fig. 6, 42) can target the WNT/β-catenin/TCF signaling pathway to inhibit cancer cell migration and growth⁵⁶. These anti-fungal agents originally targeted fungal pathogens, but are also found to treat cancer in vivo. Their therapeutic targets in humans are also like other drugs like those targeting the WNT, PI3K/AKT/mTOR and ROS pathways.

Figure 6.

Chemical structures of 38–43 as microbiological agents for repurposing in cancer therapy.

3.2.3. Synthetic anti-bacterial drugs

Ciprofloxacin (Fig. 6, 43) belongs to the second generation of synthetic quinolone anti-bacterial agent with a broad spectrum of anti-bacterial activity. ATP-binding cassette subfamily B member 1 (ABCB1) is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients, ciprofloxacin can reverse MDR by inhibiting the ABCB1 efflux function⁵⁷. In addition, ciprofloxacin can promote cell apoptosis and regulate the function of immune cells for cancer treatment. According to research, ciprofloxacin is able to promote the production of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and the polarization of CD86⁺CD206^– macrophages, while inhibiting the polarization of CD86⁺CD206^– macrophages which plays an important role in tumor regulation. Ciprofloxacin may inhibit liver cancer by upregulating the expression of CD86⁺CD206^– macrophages⁵⁸. Thus, ciprofloxacin has a potential to be developed as a combination anticancer therapy. Microbiological agents are promising candidates for drug repurposing for cancer therapy, but further clinical development and research are required to translate these findings into clinical applications.

3.3. Antibiotics repurposing for cancer therapy

Antibiotics are used to treat bacterial infection, but they are also being studied for their ability to target cancer cells. Those exhibiting antitumor activity including β-lactams, tetracyclines and anti-tuberculosis drugs. Bedaquiline (Fig. 7, 44) is an FDA-approved antibiotic that is used to treat multi-drug resistant pulmonary tuberculosis (TB) by inhibiting the bacterial ATP-synthase⁵⁹. Due to eukaryotic mitochondria originally evolving from engulfed aerobic bacteria, it is reasonable to hypothesize that bedaquiline might target the mitochondrial ATP-synthase and lead to mitochondrial dysfunction and ATP depletion in cancer cells⁶⁰. In fact, bedaquiline was found to inhibit mitochondrial oxygen consumption, glycolysis in MCF7 breast cancer cells and block the propagation and expansion in MCF7-derived stem-like cancer cells (CSCs). Mitochondria play an important role in cancer treatment and offer potential applications for mtDNA modifications as novel anticancer targets⁶¹. Therefore, bedaquiline could be a promising chemotherapeutic for cancer, but further pre-clinical studies and human clinical trials in cancer patients are needed to confirm this.

Figure 7.

Chemical structures of 44–47 as antibiotics for repurposing in cancer therapy.

Tetracyclines drugs like doxycycline (Fig. 7, 45) and tigecycline (Fig. 7, 46) could target oxidative mitochondrial metabolism to prevent the propagation of cancer. They could induce cell cycle arrest, apoptosis, autophagy, and oxidative stress in cancer, and inhibit cell proliferation, migration, invasion, and angiogenesis through targeting PI3K/AKT, AMPK-mediated mTOR, cytoplasmic P21, and WNT/β-catenin signaling⁶².

Clofoctol (Fig. 7, 47) was used for the treatment of upper respiratory tract infections in France and Italy by alteration of bacterial membrane permeability owing to its hydrophobic nature¹³¹. Now, it has been reported that clofoctol can inhibit protein translation in mammalian cells, so it could serve as a potential anticancer drug¹³². Clofoctol could inhibit cancer cell growth through activation of the unfolded protein response (UPR) pathway in the endoplasmic reticulum (ER), which is a major cellular organelle for folding and maturation of secretory proteins. If misfolded proteins accumulate over the limit of the capacity of ER-associated degradation, the UPR pathway will be activated by one of three sensing proteins, either IRE1, PERK or ATF6, to improve the protein folding and down-regulate protein translation in the ER to reduce the ER folding load. There is already evidence suggesting that many types of cancer cells have higher levels of ER stress, so the UPR pathways are already active to maintain cellular homeostasis. Therefore, further increasing the ER stress could result in overload of the stress responses in cancer cells and in turn induce cell cycle arrest or cell death. Clofoctol induces ER stress and activates all three UPR pathways in PC3 cells, thus inhibiting protein translation and inducing G1 phase cell cycle arrest⁶³. Antibiotics are attractive compounds for their ability to target cancer cells and inhibit bacterial infection. The repurposing of antibiotics to treat human tumors is based on a reasonable hypothesis that they target a new mechanism, namely, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. In these studies, antibiotics show promising antitumor effect and will be worthwhile to make expand efforts.

3.4. Antiviral drugs repurposing for cancer therapy

Antiviral drugs are used to treat a group of viruses inducing serious diseases. Apart from the human immune deficiency virus (HIV), most viral diseases are self-limiting illnesses. For example, ritonavir (Fig. 8, 48) shows a potential use for ovarian cancer, glioblastoma, and lung cancer with additive effects in conjunction with conventional chemotherapeutic regimens^133,134. Ritonavir was found to exert antitumor effects by inducing cell cycle arrest with decreasing expression of G1 phase cyclins and cyclin dependent kinases (CDKs), and by promoting apoptosis by increasing the expression of BAK and inhibiting BCL-2 in ovarian cells in a dose dependent manner. Inhibition of AKT pathway also leads to cell apoptosis and inhibits cell migration and invasiveness for cancer therapy⁶⁴. Nelfinavir (Fig. 8, 49) can improve current approaches of targeted melanoma therapy. MAPK-pathway inhibitors (MAPKi) are usually used for treating melanoma, pancreatic cancer, and rectal cancer, but long-term BRAF and MEK inhibition will induce drug resistance in melanoma. It has been found that the acquired resistance is induced by the upregulation of the melanoma survival oncogene MITF which is regulated by PAX3. Nelfinavir can decrease MAPKi-induced drug tolerance by suppressing PAX3 and MITF expression in BRAF mutant melanomas. The PAX3–MITF axis is a good target for MITF-driven drug tolerance and the expression of PAX3 is tightly regulated by BRAF-initiated MAPK signaling through SMAD2/4 and the SKI complex which is controlled by transforming growth factor b (TGF-b). Therefore, targeting SMAD2/4 and the SKI complex to keep them in a steady-state condition is correlated with a reduction in PAX3 and MITF expression⁶⁵. In clinical research, combination therapy of nelfinavir with short course hypofractionated radiotherapy (SCHRT) increases tumor perfusion and radiosensitizes tumors in rectal cancer⁶⁶.

Figure 8.

Chemical structures of 48–51 as antiviral drugs for repurposing in cancer therapy.

Maraviroc (Fig. 8, 50) is another antiviral drug repurposed for triple-negative breast cancer (TNBC) therapy which acts as a C-C chemokine receptor 5 (CCR5) inhibitor to block lymphangiogenesis and lung metastasis. It has been shown that interleukin-6 (IL-6) and C-C chemokine ligand 5 (CCL5) play important roles in TNBC tumor growth and metastasis. Therefore, CCR5, which is widely expressed on tumors, is a new therapeutic target for metastatic cancers like breast and colon cancer in clinical trials. Thus, maraviroc could be repurposed for cancer treatment⁶⁷. In addition, maraviroc combined with other anticancer drugs may exert unexpected effects. In one study, a combination of tocilizumab and maraviroc decreased cellular viability, and a combination of maraviroc and cMR16-1 resulted in greater inhibition of tumor growth compared to each single agent⁶⁸. Compounds with structure modifications might have enhanced antitumor effects as well. For example, 8-hydroxy-[1,6]naphthyridines (L-870810) (Fig. 8, 51) is one of a promising class of antiretroviral drugs developed by Merck Laboratories. Optimization of L-870810 shows significant cytotoxicity in a panel of cancer cell lines and effectively inhibits select oncogenic kinases⁶⁹. Therefore, it is possible to apply it to cancer therapy, but this requires more verification. Antiviral drugs may reveal antitumor activity by examining clinical data retrospectively and finding decreased incidence rates, for example, of HIV-related cancers after taking antiviral drugs. These clinical data suggest that antiviral drugs have potential to treat cancer.

3.5. Anti-inflammatory drugs repurposing for cancer therapy

Anti-inflammatory drugs have anticancer effects because inflammation can also induce cancer. They mainly exhibit anticancer activity through inhibition of cyclooxygenase (COX) enzymes¹³⁵. For example, aspirin (Fig. 9, 52) is commonly used for the treatment and prevention of atherosclerotic disease. In 1988, it was first shown to reduce the risk of colorectal cancer in a clinical trial. Since then, several studies have been demonstrated that aspirin can reduce the incidence of several different cancers. The anti-neoplastic effects of aspirin have been attributed to its inhibition of COX-1 and COX-2 enzymes which promote carcinogenesis through synthesis of PGE2⁷⁰. PGE2 effects are mediated by E-prostanoid (EP) receptor signaling impacting on G-protein coupled receptors to promote proliferation, invasion, secretion of angiogenic factors and inhibition of apoptosis. In one study, knocking out the gene for COX-2 or any of several PGE2 receptor genes resulted in decreased intestinal tumor incidence in mouse models of colorectal cancer (CRC). In addition, phosphatidylinositol 3-kinase (PI3K) and WNT/β-catenin/TCF signaling pathways play a major role for aspirin inhibition of carcinogenesis⁷¹. The WNT/β-catenin/TCF signaling pathway is activated by extracellular WNT ligand binding to surface receptors, followed by β-catenin translocating to the nucleus and binding to TCF protein, finally affecting cell proliferation and migration. TCF activity is related to the transcription of a TCF-responsive reporter gene and the WNT/TCF transcriptional target CYCLIN D1. Aspirin can attenuate TCF-responsive reporter gene activity and downregulate CYCLIN D1 by modulating TCF activity. In clinical trials, aspirin could enhance the anticancer effects in non-small cell lung cancer by targeting GRP78 activity, and therefore it could be a potential drug for novel anticancer treatments.

Figure 9.

Chemical structures of 52–55 as anti-inflammatory drugs for repurposing in cancer therapy.

Auranofin (AUR) (Fig. 9, 53) is an FDA-approved anti-rheumatoid arthritis (anti-RA) drug. Recently, it was reported that AUR potently upregulates hepcidin expression and induces ferroptosis both in vitro and in vivo, which is related to some diseases⁷². Its canonical signaling pathways to regulate iron, including the BMP/SMAD and IL-6/JAK/STAT3 pathways, play indispensable roles in mediating AUR's effects. Interestingly, AUR also exerts an effect on glioblastoma multiforme by inhibiting cathepsin B expression, which may inhibit glioblastoma growth, and by inhibiting thioredoxin reductase (TXNRD) activity, thus increasing intracellular ROS and resulting in cell death. However, AUR shows only moderate activity as a single agent in clinical applications in cancer treatment. Celecoxib (CE) (Fig. 9, 54) was unexpectedly identified as potently enhancing the anticancer activity of AUR in vitro and in vivo through a high-throughput screening of the FDA-approved drug library. The AF/CE combination induces severe oxidative stress that causes ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation in tumors⁷³. According to one study, CE promotes ROS generation by disrupting the mitochondrial respiration chain, but the exact targets of celecoxib in the mitochondria remain unclear. It was reported that CE could reduce cell viability by induction of DNA damage, leading to P53-dependent G1 cell cycle arrest and P53-dependent autophagy by downregulation of NF-κB, caspase-9, BAX and BCL-X_L⁷⁴.

Ibuprofen (Fig. 9, 55) has a long history in research seeking new anticancer agents. Previously, S ibuprofen was found have anti-inflammatory effects, while the R form is inactive, but it could mediate anticancer effects in humans by converting R ibuprofen into S ibuprofen. A recent study by the National Institutes of Health (INSA) found that ibuprofen has an anticancer effect on colon cancer and inhibits malignant cell growth. In their research, ibuprofen's anticancer mechanism is to prevent cancer cells from producing tumorigenic variants of certain proteins. Additionally, a combination of ibuprofen and celecoxib showed effects on cancer in the liver of Walker-256 tumor-bearing rats by increasing the expression of genes associated with fatty acid oxidation (PPARα and CPT1) and consequently the production of ATP to normalize the energy status⁷⁵. Tumors are caused by repeated stimulation of inflammation, and therefore chronic inflammation is often followed by neoplasia and inflammatory cells are also present in tumor tissues as well. Some inflammatory factors can increase the invasive ability of malignant tumor cells. Thus, inflammation is inextricably linked to tumorigenesis, and anti-inflammatory drugs could represent a resource for discovering antitumor drugs.

3.6. Anti-neurodegenerative drugs repurposing for cancer therapy

Neurodegenerative diseases result from the loss of neurons or their myelin sheaths. Commonly seen disease mainly including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS)¹³⁶. The endogenous cholinergic system plays a key role in neuronal cells by suppressing neurite outgrowth and myelination and is found to favor tumor growth in some cancer cells. Drugs for treating neurodegenerative disease have been found to have antitumor effects as well¹³⁷. For example, benztropine (Fig. 10, 56) is currently a second-line drug for the treatment of Parkinson's disease, but has been discovered to possess anticancer activity by a tumor spheroid-based multiplex phenotypic screening system. It was found to be an effective compound for inhibition of in vitro tumor spheroid formation and cancer cell survival. Benztropine could suppress tumor growth, reduce circulating tumor cells and metastasis by acting on SLC6A3/DAT and reducing STAT3⁷⁶. In addition, matrix metalloproteinases (MMP), especially MMP9, are often highly expressed in human cancers and are related to the poor prognosis of patients. In further studies, MMPs were found to enhance tumor progression. The promoters of MMPs contain binding sites for oncogenic transcription factors like STAT, NF-κB and the TCF/β-catenin complex. Benztropine can suppress MMP expression by regulating these transcription factors to inhibit cancer cell invasiveness. Additionally, benserazide (Fig. 10, 57) was reported to suppress tumor growth by inhibiting HK2 which plays a vital role in tumor initiation and maintenance. In addition, benserazide could reduce glucose uptake, lactate production and intracellular ATP levels, and cause cell apoptosis and increased loss of mitochondrial membrane potential as well⁷⁷.

Figure 10.

Chemical structures of 56–60 as anti-neurodegenerative drugs for repurposing in cancer therapy.

Donepezil (Fig. 10, 58) is used for Alzheimer's disease, but it also shows antitumor activity by increasing cell mitosis duration or inducing cell mitosis arrest⁷⁸. Memantine (Fig. 10, 59) also shows to be effective on cancer through inhibition of proliferation and induction of autophagy mediated by NMDAR1⁷⁹. Riluzole (Fig. 10, 60) is an amyotrophic lateral sclerosis (ALS) drug, the action of which was also investigated on hepatocellular carcinoma, where it was found to suppress cell proliferation in liver cancer and to induce the caspase-dependent apoptosis pathway and G2/M cell cycle arrest⁸⁰. In addition, a new antitumor target pathway for riluzole is to inhibit the release of cellular glutamate, which decreases the production of cellular GSH and increases the production of ROS, which in turn results in cell death as well. Neurodegenerative diseases are characterized by deposits of misfolded proteins in the brain, and one treatment approach is to regulate them by inhibiting poly ADP-ribose polymerase (PARP), which is also a target of cancer treatment. Therefore, anti-neurodegenerative drugs could be studied for treating cancer as well. However, more detailed research is necessary for drug repurposing to utilize anti-neurodegenerative drugs to treat cancer.

3.7. Antipsychotic drugs repurposing for cancer therapy

Antipsychotic drugs are commonly prescribed for the treatment of psychosis, schizophrenia, bipolar disorder, and other diseases, but many studies have indicated that some of these drugs may also mediate antitumor activity. In the 1950's, chlorpromazine (CPZ) (Fig. 11, 61), the first drug to treat psychosis, was found by accident in clinical trials, which has opened a new era of modern psychotropic drug therapy. According to the structure and pharmacological mechanisms of action, antipsychotics can be divided into first and second generation drugs¹⁶. CPZ, belonging to the phenothiazine class of anti-psychotic drugs, was a first-generation anti-psychotic used in the late sixties and early seventies as the most important drug for schizophrenia and psychotic disorders. In the meantime, CPZ has been identified as a potential candidate for drug repurposing in cancer. It was found that it exerted antitumor effects linked to the inhibition of cancer cell growth and proliferation by regulating the expression of related proteins and interfering with mitochondrial processes. In glioma cell lines, CPZ exerts its anti-proliferative effect by inducing autophagic cell death through inhibition of the PI3K/AKT/mTOR pathway. In addition, CPZ can increase the expression of the cyclin-dependent kinase (CDK) inhibitor P21, which thus causes cell cycle arrest in the G2/M-phase. In colorectal cancer cells, CPZ induces apoptosis via up-regulation of P53. Additionally, CPZ inhibits the mitotic kinesin KSP/Eg-5, resulting in mitotic arrest and cell cycle inhibition⁸¹.

Figure 11.

Chemical structures of 61–68 as antipsychotics for repurposing in cancer therapy.

Fluphenazine hydrochloride (Flu; Fig. 11, 62) is another commonly prescribed antipsychotic drug. In one study, Flu showed potential for the treatment of TNBC and its brain metastases by inducing G0/G1 cell cycle arrest and promoting mitochondria-mediated intrinsic apoptosis in vitro. Moreover, Flu could suppress the growth and proliferation of breast cancer cells by decreasing the expression of p44/42 ERK and phosphorylated AKT, which are two key molecules in RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways in both TNBC cell lines. In addition, Flu could induce G0/G1 phase arrest in TNBC cells through downregulation of expression of CDK2, CDK4 and CYCLIN D1 and up-regulation of P21 and P27⁸². According to one study, Flu might induce apoptosis via the mitochondria-mediated intrinsic apoptotic pathway and suppress TNBC cell migration and invasion in vitro. Penfluridol (PF) (Fig. 11, 63) also shows to exert antitumor effects in vivo by suppressing tumor growth via AKT-mediated inhibition of the transcription factor GLI1. In glioma cells, PF treatment could reduce cancer cell migration and invasion by decreasing integrin α6 and uPAR levels, which was mediated by downstream activation of FAK, paxillin, RAC, and ROCK proteins. In breast cancer cell lines, PF treatment inhibited the expression and activation of these downstream proteins. Integrins are an important therapeutic target in various cancer types related to cancer cell metastasis. Hence, reducing integrin expression might suppress the expression of the epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1 to inhibit the cancer metastasis. Furthermore, a combination of PF and temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo⁸³.

Olanzapine (Fig. 11, 64) is a second-generation anti-psychotic drug mainly used in clinical treatment. It can inhibit cancer cell proliferation, migration and anchorage-independent growth and induce apoptosis, necrosis and cytostasis in tumor cells. It also disrupts cholesterol homeostasis to kill cancer cells⁸⁴. Similarly, risperidone (Fig. 11, 65) also shows promise as a potential adenocarcinoma treatment by slowing proliferation of PC3 prostate cancer cells⁸⁵. Clomipramine (Fig. 11, 66) is repurposed for cancer therapy by activating phosphorylation of c-JUN and increasing cytochrome c release and caspase-3-like activation, thus leading to apoptosis of cancer cells⁸⁶. SH-I-14 (Fig. 11, 67) and KRICT-9 (Fig. 11, 68) are used to treat dementia, but also have new indications for cancer by inhibiting STAT3⁴⁷. Antipsychotic drugs are an important group for repurposing and show promising anticancer effects. Hence, more research is justified to identify their mechanism of action.

3.8. Antidepressants repurposing for cancer therapy

Antidepressants are a group of psychotropic drugs used primarily for the treatment of psychiatric disorders characterized by mood depression. Antidepressants were first introduced in the 1950s, and mainly used to treat depression and various depressive states. Notably, several studies have reported that antidepressants may have antitumor activity. For example, tricyclic antidepressants (TCAs) are the most common first-generation antidepressants containing three fused rings in their structure. Imipramine (Fig. 12, 69) exerts effects on cancers such as glioma, small cell lung cancer (SCLC) and others⁸⁷. Imipramine induces cell autophagy and cell death by inhibiting P2RY12⁴¹. Trimipramine (Fig. 12, 70) and amitriptyline (Fig. 12, 71) are also used to treat cancer⁸⁸. Recently, it has been reported that combining an antidepressant and a drug derived from vitamin A is a promising way to treat leukemia. All-trans retinoic acid (ATRA) (Fig. 12, 72) has been successfully used to treat acute myeloid leukemia (AML), but it is not effective for other common types of AMLs⁸⁹. Tranylcypromine (Fig. 12, 73) could also exert effects on AMLs by inducing the leukemic cells to mature and die naturally. Selective serotonin reuptake inhibitors (SSRI) are a new class of antidepressants which were first tested in clinical trials in the 1980s. They reduce cell proliferation and induce apoptosis in cancer cells and downregulate pAKT to mediate the synergistic anti-proliferative interactions with other chemotherapeutic drugs⁹⁰. For example, fluoxetine (Fig. 12, 74) induces autophagic cell death via eEF2K–AMPK–mTOR–ULK pathway in triple negative breast cancer⁹¹. Citalopram (Fig. 12, 75), paroxetine (Fig. 12, 76) and sertraline (Fig. 12, 77) are all SSRIs and show anticancer activity as well92, 93, 94^,138. Proscillaridin A (ProA) (Fig. 12, 78) exerts antitumor effects through GSK3β activation in WNT pathway and alteration of microtubule dynamics in glioblastoma⁹⁵. Valproic acid (VPA; Fig. 12, 79) inhibits histone deacetylase to reduce cancer cell proliferation and induce apoptosis, as well as inducing differentiation and inhibiting angiogenesis in cancer⁹⁶. Antidepressants mainly inhibit reuptake of amine neurotransmitters, but their antitumor mechanism are more complicated, and more effort should be required for drug repurposing.

Figure 12.

Chemical structures of 69–79 as antidepressants for repurposing in cancer therapy.

3.9. Other drugs repurposing for cancer therapy

3.9.1. Antidiabetics

In addition to the above drugs, there are many others that could be repurposed for cancer as well. For example, some of the drugs for type II diabetes show anti-neoplastic effects. Metformin (Fig. 13, 80) is a classic drug for diabetes, and shows effects on several cancers like glioblastoma multiforme, non-small cell lung cancer, rectal cancer, prostate cancer, and ovarian cancer. It might be able to treat cancer by inducing autophagy, apoptosis, and cell death via activating AMPK. In addition, it downregulates the AKT–mTOR signaling pathway and inhibits CLIC1 activity to induce G1 cell arrest⁹⁷. Pioglitazone (Fig. 13, 81) is also an anti-diabetes drug that might be used to treat lung cancer by its highly selectivity for peroxisome proliferator-activated receptor gamma (PPARγ). It can inhibit β-catenin expression to block the WNT signal pathway and reduce cell viability and proliferation, and induce apoptosis^98,99. Repaglinide (Fig 13, 82), rosiglitazone (Fig. 13, 83), buformin (Fig. 13, 84), ciglitazone (Fig. 13, 85) and phenformin (Fig. 13, 86) all have anti-hyperglycemic effects and show anticancer activity^{100,101,139,140}.

Figure 13.

Chemical structures of 80–97 as other drugs for repurposing in cancer therapy.

3.9.2. Anthelminthic drugs

Anthelminthic drugs are also a class of repurposed drugs for cancer treatment. For example, mebendazole (Fig. 13, 87) inhibits proliferation of cancer cell by inducing tubulin depolymerization resulting in mitotic arrest. It leads to P53 accumulation and cell cycle arrest in the G2/M phase, consequently inducing cell apoptosis mediated by cytochrome c, caspase-9, and caspase-3. Additionally, it inhibits TNIK, which is an activator of the WNT/TCF/β-catenin transcriptional program. Inhibition of the BRAF–MEK–ERK signal pathway, which is related to cell growth, proliferation, and survival, is another target of this drug. Mebendazole also upregulates the expression of pro-inflammatory genes to reduce levels of VEGF and VCAM-1 and eventually inhibit tumor growth¹⁰². Albendazole (Fig. 13, 88) is also repurposed for antitumor treatment to target the altered redox status of cancer cells, which is an interesting approach for new cancer therapy. It promotes the generation of ROS, thereby oxidizing DNA at C4 of deoxyribose causing DNA breakage and triggering apoptosis as well as inducing cell death by increasing P53 and BAX expression, at the same time as diminishing BCL-X_L expression. Albendazole activity appears to be related to tubulin polymerization inhibition which is responsible for separation of duplicated chromosomes during cell division, thereby promoting cell cycle arrest at the G2/M phase¹⁰³. Flubendazole (Fig. 13, 89) can target ATG4B in breast cancer to induce cell autophagy¹⁰⁴. Additionally, it was found to up-regulate the expression of EVA1A, which is related to cell autophagy and apoptosis in triple-negative breast cancer¹⁴¹. Niclosamide (Fig. 13, 90) is an anti-parasitic drug showing antitumor activity in hepatocellular carcinoma through reversing the HCC gene expression signature, based on computational modeling of public data¹⁰⁵. In this way, niclosamide and its ethanolamine salt was discovered to bind to the cell division cycle 37 (CDC37) protein and disrupt its interaction with heat shock protein 90 (HSP90) to inhibit tumor cell proliferation. Simultaneously, it also reduces the expression of proteins in the WNT/β-catenin, STAT3, AKT–mTOR, EGFR–RAS–RAF signaling pathways, which are fundamental to HCC development^106,107.

3.9.3. Other drugs

Disulfiram (Fig. 13, 91) is used for treating alcoholism but may be repurposed to treat glioma, NSCLC, CRC, and esophageal squamous cell carcinoma. The molecular anticancer target of disulfiram is an adaptor of the human ubiquitin selective protein segregase P97, which plays a role in the turnover of proteins orchestrating stress-related signaling pathways¹⁰⁸. AM404 (Fig. 13, 92) is a metabolite of acetaminophen with antibacterial activity, and has been validated as an inducer of cell differentiation and inhibitor of neoplastic cell growth in both in vitro and ex vivo models. It exerts anticancer activity by suppressing oncogenic FBXL5 in colorectal cancer cells to regulate the PTEN/PI3K/AKT signal pathway and HIF-1 transcriptional activity which then results in colon cancer death. To further confirm this result, AM404 is sensitive to FBXL5-knockout cells and causes further additive effects by inhibiting cell migration¹⁰⁹. Salbutamol (Fig. 13, 93) is used for bronchial asthma, but is found also to affect cancer by activating the β2 adrenoreceptor¹¹⁰. Raloxifene (Fig. 13, 94) and bazedoxifene (Fig. 13, 95) are also used to treat osteoporosis with potential usefulness for cancer therapy by inhibiting IL-6/GP130 interactions in redirection studies¹¹¹. Cationic amphiphilic antihistamines have been studied for their anticancer actions as well; they were found to induce lysosomal membrane permeabilization and cell death preferentially in cancer cells¹¹². Thiabendazole (Fig. 13, 96) might be a potential new chemotherapeutic for cancer by disrupting vascular networks¹¹³.

More recently, immunotherapy has been the hot topic of cancer treatment and some old drugs have also been repurposed for potential cancer immunotherapy by targeting PD-1/PD-L1, CD47, and TIGIT/PVR. For instance, niclosamide can enhance the cancer cell lysis mediated by T cells in the presence of PD-L1 blockade and delayed the tumor growth and increase the survival which is associated with the increase of tumor infiltrating T cells and granzyme B release. It suggests that the combination therapy of niclosamide and PD-1/PD-L1 blockade is worth to be further studied in clinic¹⁰⁷. In addition, azelnidipine (Fig. 13, 97), an anti-hypertensive drug approved by the FDA, can be repositioned for cancer immunotherapy by dual blocking CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vivo, azelnidipine alone or combined with irradiation can significantly inhibits the growth of MC38 tumors and CT26 tumors by enhancing the infiltration and function of CD8⁺ T cell in tumor¹¹⁴. As mentioned above, an increasing number of drugs have been repurposed for cancer immunotherapy, indicating a promising potential on cancer therapy.

4. Concluding remarks and future perspectives

Drug repurposing is becoming an attractive therapeutic strategy for exploiting more approved non-oncology drugs to improve potential cancer therapy, which, in turn provides a new avenue for discovery of candidate small-molecule compounds for cancer drug development. It is well-known that discovery of novel antitumor agents is costly and time-consuming; therefore, new strategies for drug repurposing may drastically reduce the research and development cycle because of their safety, toxicity, and pharmacological properties. Accordingly, many FDA-approved drugs or experimental drugs used for treating other diseases can be reused for exploring their potential antitumor effects¹⁴². Repurposed drugs can be further investigated according to their off-target effects, which might be inversely related to their therapeutic target in cancer¹¹⁰. Based on the retrospective clinical data, prior knowledge of the side effects of old drugs may have a huge therapeutic potential on different types of human cancers. Interestingly, some of these old drugs have the same target that is related to the of occurrence two or more different diseases; therefore, a drug which retains its original indication can also be used to treat human cancers¹⁴³.

Presently, a set of new technologies has been emerging for drug repurposing, which would help identifying novel druggable targets for old therapeutic agents. For instance, large-scale multi-omics sequencing containing genomics, proteomics, transcriptomics and phenomics can help understand disease mechanism, elucidate drug mechanism of actions and identify new use of old drugs. Usually, multi-omics is an approach to identify the drug–disease relationships by comparing drug gene expression profiles and disease gene expression profiles with the help of CMap, a key source of data to construct a detailed map for functional associations among diseases, genetic perturbations, and drug actions. For example, antidepressant drugs have been identified for the treatment of small cell lung cancer by using multi-omics sequencing. Another approach is to discover small-molecule drugs that provoke similar transcriptional responses for they can share similar mode of action in one disease. In addition, multi-omics sequencing analyzes gene expression profiles of cancer cells and identify a few of mutated cancer genes that are associated with drug sensitivity may serve as potential biomarkers of drug response by using hundreds of clinical or preclinical drugs for large-scale screening of human cancer cell lines. In addition, genome-wide positioning systems network (GPSnet) algorithms can be used to identify the similarity between drug targets and disease proteins in human protein–protein interaction (PPI) groups, which may be conducive to determining repurposed drug action targets¹⁴⁴. With the increasing focus on drug repurposing, there have accumulated a plenty of information about these researches than ever before, therefore it is difficult for scientists to process data and find useful information by themselves. But data processing advances have made a rapid progress in artificial intelligence (AI), which has been also used in drug repurposing by outsource our reasoning to a machine intelligence when it comes to the analysis of multisource and multidimensional data¹⁴⁵. Applying a particular AI algorithm in drug repurposing is a sequential process that requires the proper definition of the problem domain. Thus, the first step is to constructing a model which ensures the choice of the machine learning method appropriate for the problem under study. Once the model and the data sets have been established, one may proceed to model training and evaluation. For example, machine learning models implementing AI methods have been successfully applied in several aspects of the virtual screening including structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS). These approaches greatly improve the drug repurposing process and decrease the cost of drug discovery. Additionally, combinations of multi-omics and AI approaches can be used to clarify the key signaling pathways of cancer progression and metastasis, and further identify druggable targets and relevant mechanisms. They can be applied for modeling biological processes to identify new disease-relevant targets and drug phenotype associations. For example, structure-based virtual screening methods have greatly decreased the costs of drug redirecting processes. Also, molecular docking and ligand-based chemo-informatics can be used to elucidate new drug–target interactions¹⁴. More importantly, CRISPR/Cas9 genome editing technology has been developing into a robust tool for identifying drug targets for future cancer therapy by knock-down and knock-out specific genes in cancer cells^95,146. High-throughput screening on cell phenotype can be used to discover systematic target–phenotype relationship by screening thousands of compounds in numerous types of cancer cells.

In conclusion, we summarized about 100 small-molecule non-oncology drugs with therapeutic potential, including cardiovascular drugs, microbiological drugs, small-molecule antibiotics, anti-viral drugs, anti-inflammatory drugs, anti-neurodegenerative drugs, antipsychotic drugs, antidepressants, and other drugs in cancer. Moreover, we discussed their potential targets and relevant key pathways for cancer treatment. Although the current success rate of drug reuse is low, it is a promising avenue for discovery of small-molecule drugs for fighting human cancers. With the development of newer biological, chemical, and computational technologies, the bottleneck of drug repurposing should be ultimately overcome; thereby providing a new perspective from old non-oncology drugs to new anticancer agents in the future.

Acknowledgments

This work was supported by Natural Science Foundation of China (Grant Nos. 82172649, 81873089, 31970374, 81803365, and 81873939), The National Key Research and Development Program of China (2021YFE0203100), Key R&D Program of Sichuan Province (Grant No. 2021YFS0046, China), and Applied Basic Research Programs of Science and Technology Department of Sichuan Province (Grant No. 2020YJ0285, China). And, we also thank Wuhan Edisprings Technology & Culture Co., Ltd. (P-202104271435368589) for polishing English language in this manuscript.

Author contributions

Lan Zhang, Bo Liu and Haiyang Yu revised, and submitted the manuscript. Leilei Fu, Wenke Jin, Jiahui Zhang and Lingjuan Zhu wrote the manuscript. Leilei Fu, Wenke Jin, Jia Lu, Yongqi Zhen and Liang Ouyang collected the information. All the authors approved the final manuscript.

Conflicts of interest

The authors declare that they have no conflict of interest.