Cancer remains one of the leading causes of mortality worldwide, despite advances in conventional treatments. However, the high costs, limited efficacy, and side effects associated with these therapies have fueled interest in alternative approaches. One promising avenue is drug repurposing—the application of existing drugs, originally developed for non-cancerous conditions, to cancer treatment.
Repurposed drugs often act on cancer by exploiting vulnerabilities in cancer cells. Common mechanisms include:
Interruption of Cancer Pathways: Non-oncology drugs such as metformin and statins can modulate pathways critical for tumor growth, including PI3K/AKT/mTOR and AMPK.
Targeting Tumour Metabolism: Drugs like metformin, originally for diabetes, inhibit mitochondrial respiration and reduce ATP production, selectively affecting cancer cells’ energy metabolism.
Enhancing Immune Surveillance: Anti-inflammatory drugs such as aspirin may promote immune recognition of tumours by reducing the immunosuppressive tumour environment.
Inhibiting new blood vessel formation: Drugs like propranolol and thalidomide have shown potential to inhibit blood vessel formation, starving tumours of nutrients and oxygen.
Numerous repurposed drugs have shown promise in preclinical and clinical studies. Below are examples of widely studied candidates:
Metformin: Commonly used to treat type 2 diabetes, metformin has demonstrated antitumor effects by activating AMPK and inhibiting mTOR. Studies suggest that diabetic patients taking metformin have a lower risk of developing certain cancers, including breast and pancreatic cancers (e.g., Noto et al., Diabetes Care, 2012; Zhang et al., Cancer Prevention Research, 2011). However, this analysis is mainly based on observational studies not randomised trials which are needed to confirm this potential benefit.
Aspirin: As an anti-inflammatory drug, aspirin reduces the risk of colorectal cancer and other malignancies. Evidence indicates that long-term aspirin users have a reduced incidence of colorectal and possibly other cancers (e.g., Rothwell et al., Lancet, 2010; Chan et al., JAMA, 2005).
Indomethacin, traditionally used as a nonsteroidal anti-inflammatory drug (NSAID) for pain and inflammation, has garnered interest as a repurposed medication for cancer therapy. Emerging research suggests that indomethacin may exhibit anticancer properties through its ability to inhibit cyclooxygenase (COX) enzymes, which play a role in inflammation and tumor progression. Additionally, indomethacin has been shown to induce apoptosis (programmed cell death) in cancer cells and inhibit angiogenesis, the process through which tumors develop new blood vessels to supply themselves with nutrients. Studies have also highlighted its potential to modulate signaling pathways involved in cancer cell proliferation and metastasis. As a result, indomethacin is being explored for its role in combination therapies and as a targeted approach in oncology, offering a promising avenue for developing novel cancer treatment strategies (Chun et al., 2019, Indomethacin as a repurposed drug for cancer therapy: Mechanistic insights and therapeutic potential. Cancer Treatment Reviews, 74, 34-43.
Statins: Originally designed to lower cholesterol, statins exhibit antitumor activity through inhibition of the mevalonate pathway. Observational studies suggest a decreased cancer risk among long-term statin users, particularly for colorectal and prostate cancers (e.g., Nielsen et al., Cancer Epidemiology Biomarkers & Prevention, 2012; Singh et al., Clinical Cancer Research, 2013).
Ivermectin: Primarily an antiparasitic drug, ivermectin has shown potential to disrupt multiple cancer pathways, including WNT/β-catenin and STAT3 signaling. While there is no robust evidence yet for reduced cancer risk among ivermectin users, its preclinical antitumor properties are under investigation (e.g., Juarez et al., Pharmacological Research, 2018).
Mebendazole: An anti-helminthic drug, mebendazole exhibits antitumor properties by disrupting microtubule formation, inducing apoptosis, and impairing cancer cell division. There is limited evidence that long-term use correlates with reduced cancer risk, though studies are ongoing (e.g., Mukhopadhyay et al., Cancer Letters, 2002).
Fenbendazole: Another anti-helminthic drug licensed for animal use§, fenbendazole has demonstrated anticancer effects by targeting microtubule dynamics, inducing cell death, and altering cancer cell metabolism. Evidence linking fenbendazole to lower cancer risk in its traditional use is currently anecdotal (e.g., Lewis et al., Journal of Natural Products, 2011).
Doxycycline: A broad-spectrum antibiotic, doxycycline has exhibited anticancer properties by inhibiting mitochondrial biogenesis and metalloproteinases. There is no substantial epidemiological data linking doxycycline use to reduced cancer incidence (e.g., Lamb et al., Frontiers in Oncology, 2015).
Thalidomide: Originally developed as a sedative, thalidomide has shown promise in oncology for its anti-angiogenic and immunomodulatory effects. It is not commonly associated with reduced cancer risk in its original indications (e.g., Bartlett et al., Blood, 2004).
Propranolol: A beta-blocker for cardiovascular conditions, propranolol has been investigated for its ability to inhibit new blood vessel formation. Some studies suggest a reduced cancer risk in long-term beta-blocker users (e.g., Chang et al., Cancer Epidemiology Biomarkers & Prevention, 2011).
Disulfiram: An alcohol-aversive drug, disulfiram exhibits anticancer activity by generating reactive oxygen species and inhibiting proteasome activity. There is no strong evidence linking disulfiram use to decreased cancer risk in patients treated for alcohol dependence (e.g., Skrott et al., Nature, 2017).
Hydroxychloroquine: An antimalarial and autoimmune disease drug, hydroxychloroquine is being explored for its ability to inhibit autophagy. No significant epidemiological data currently support reduced cancer risk in long-term hydroxychloroquine users (e.g., Wolpin et al., Cancer, 2009).
Clarithromycin: A macrolide antibiotic, clarithromycin has demonstrated anticancer effects by modulating autophagy and enhancing immune response. Its routine use does not appear to correlate with reduced cancer risk (e.g., Hirasawa et al., International Journal of Cancer, 2016).
Valproic Acid: A mood stabilizer and antiepileptic drug, valproic acid acts as a histone deacetylase (HDAC) inhibitor. Some studies suggest reduced cancer risk in long-term users, particularly for glioblastoma (e.g., Kang et al., Clinical Cancer Research, 2007).
Artemisinin and Derivatives: Originally an antimalarial drug, artemisinin and its derivatives have shown potential in targeting iron-rich cancer cells. There is insufficient evidence linking its traditional use to decreased cancer risk (e.g., Efferth et al., Molecular Cancer Therapeutics, 2006).
Despite its potential, drug repurposing faces several hurdles:
Lack of Commercial Incentive: Off-patent drugs offer limited financial returns, discouraging investment from pharmaceutical companies.
Regulatory Barriers: Demonstrating efficacy in a new indication often requires robust evidence, which can be time-consuming and resource-intensive.
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