Repurposing non-oncology drugs for cancer treatment

Submitted: 15 March 2021; Revised: 17 March 2021; Accepted: 18 March 2021; Published online first: 24 March 2021

Cancer is one of the leading causes of mortality in the world today. The development of new drugs can reduce death rates, but these products are extremely expensive in terms of development time and money. This has led to the strategy of drug repurposing; whereby drug products already approved for noncancer indications are identified as potential cancer therapies. A review, published in Signal Transduction and Targeted Therapy [1], presents various promising repurposed non-oncology drugs for clinical cancer management.

The study also summarizes approaches used for drug repurposing and discusses the main barriers to uptake [2].

Drug repurposing and cancer treatment: an overview

When an already approved drug product is repurposed, pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs have been already established in preclinical and phase I clinical studies. These drugs can thus rapidly progress to phase II and phase III clinical studies and the associated development time and cost of the cancer treatment can be significantly reduced.

The study notes that our understanding of cancer biology and the associated characteristics of cancer is increasing. If this is successfully coupled with repurposing studies that apply systematic screening of the entire pharmacopoeia together with advanced bioinformatics, new drugs for cancer treatment can be identified faster and at reduced cost.

The study provides a summary of non-oncology compounds that are already used for cancer therapy which are outlined below. It highlights the specific cancer characteristics targeted and distinguishes between those agents suitable for monotherapy or as drug combinations. For all the treatment options outlined, the study also provides a detailed discussion of how they effectively regulate at least one characteristic of cancer; or exert comprehensive anticancer effects by regulating multiple targets mediated by various alternative signalling routes.

Non-oncology drugs suitable for cancer monotherapy

Proliferative signal inhibitors
Cancer cells have an ability to maintain chronic proliferation. Non-oncology drugs which work by inhibiting proliferative signalling include rapamycin, prazosin, indomethacin. These had original applications as an immunosuppressant and anti-restenosis agent; in hypertension; and in rheumatic disease, respectively.

Cancer cell death inducers
Apoptosis causes cell death and prevents tumourigenesis once the cell is damaged or is placed under various physiologic stresses. Non-oncology drugs which work by inducing cell death include artemisinin, chloroquine and their related derivatives. Both of these medications are used to treat malaria and chloroquine is also a treatment for rheumatoid arthritis.

Cellular metabolism regulators
Cancer cells often have reprogrammed energy metabolism which supports malignancy by sustaining key characteristics of cancer, including uncontrolled cell proliferation, evading growth suppressors, and resisting cell death. Non-oncology drugs which work by regulating of cellular metabolism include etformin and disulfiram. The former is used to treat obese type-2 diabetes and the latter is an alcohol aversion drug.

Antitumour immunity activators
Some cancers, especially virus-induced cancers, can avoid immune surveillance or limit being eliminated by the immune system by somehow regulating both the innate and adaptive immune systems. Non-oncology drugs which work by activation of antitumour immunity include infectious disease vaccines:

Non-oncology drugs suitable for drug combination therapy

The study notes that, in some cases, compounds may not be considered for drug repurposing screening due to their low anticancer activity at known tolerated plasma drug doses described in previous indications. However, drugs that may be effective at higher dosage can be utilized through drug combination therapy. Here, a synergistic effect is produced by targeting alternative signalling pathways associated with certain cancer characteristics.

Tumour suppressor reactivators
There is now a bank of evidence that indicates a lack of crucial tumour suppressors can stimulate tumour growth. Many non-oncology drugs are being repurposed to target cancer cells that evade growth suppressors. Non-oncology drugs which work by reactivating growth suppressors include quinacrine and ritonavir. The former has previous indications for malaria, giardiasis, rheumatoid arthritis, and the latter for human immunodeficiency virus (HIV) treatment.

Cancer cell division interrupters
In cancer cells, the specialized DNA polymerase, telomerase, is expressed at high levels to counteract the normal cell growth and the division cycle. Non-oncology drugs which work by targeting telomerase and interfering with replication include curcumin, used to treat dermatological diseases, and genistein, used in the treatment of the menopause, osteoporosis and obesity.

Angiogenesis reducers
Tumour cells also stimulate angiogenesis to generate neovasculature, an important mechanism by which tumours obtain nutrients and evacuate waste products. Non-oncology drugs which work by decreasing angiogenesis include the infamous thalidomide, originally used to treat the symptoms of morning sickness, which is now used as a sedative and antiemetic drug; and itraconazole, an antifungal agent.

Cell invasion and metastasis suppressors
Tumour invasion is the mechanism by which tumour cells spread to the surrounding environment, while tumour metastasis is where cancer cells leave the primary tumour and migrate to a new location where they generate new (secondary) tumours. Some non-oncology drugs work by suppression of invasion and metastasis. These include Barberine, used to treat bacterial diarrhoea and niclosamide, an antihelminthic drug.

Genome instability disruptors
Genome instability is a major characteristic of malignancy. This allows some favourable mutant tumour genotypes to survive under stress conditions, particularly those induced by traditional cancer treatment methods, such as chemo- and radiotherapy. As such, to enhance the therapeutic index of traditional cancer therapies, drugs could be repurposed as sensitizers of genotoxic therapy to inhibit DNA damage response. Non-oncology drugs which work by disrupting the DNA damage response include spironolactone and mebendazole, which are respectively diuretic and antihelminthic drugs.

Tumour-promoting inflammation reducers
Inflammation is typically associated with tumourigenesis as it supports and accelerates tumour growth. Some non-oncology drugs work by targeting tumour-promoting inflammation. These include aspirin, a common pain and fever relief medication, and thiocolchicoside, used to treat rheumatologic and orthopaedic disorders.

Conclusions
The study stresses the urgent need to develop effective, safe, cheaper, and readily available anticancer agents. The repurposed drugs outlined that act on specific characteristics of cancer, show that there is therapeutic potential in this strategy.

Editor’s note
Oncology drugs
Proliferative signal inhibitors, cancer cell death inducers, cellular metabolism regulators, antitumour immunity activators,

Non-oncology drugs suitable for drug combination therapy
Tumour suppressor reactivators, cancer cell division interrupters, angiogenesis reducers, cell invasion and metastasis suppressors, genome instability disruptors, and tumour-promoting inflammation reducers

Competing interests: The work of the paper [1] was supported by grants from the Chinese NSFC (nos. 81821002, 81790251, and 81773143), and Guangdong Basic and Applied Basic Research Foundation (2019B030302012).

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

References
1. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui , et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020;5(1):113.
2. GaBI Online – Generics and Biosimilars Initiative. Technological approaches to drug repurposing for cancer treatment [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Mar 17]. Available from: www.gabionline.net/Generics/Research/Technological-approaches-to-drug-repurposing-for-cancer-treatment

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