Drug Repurposing
Growing evidence indeed suggests that any functional compound classified as safe for human use is likely to have multiple therapeutic applications.
Nowadays, the trend is shifting from discovering new chemical entities from plants, marine organisms, and animals to repurposing previously reported compounds. Repurposing is the process of using drugs that have been previously reported and approved by regulatory agencies such as the FDA, the European Medicines Agency (EMA), and the Medicines and Healthcare Products Regulatory Agency (MHRA) for a new therapeutic use. It is a less expensive and faster method of bringing effective medicines to patients. Furthermore, this technique helps overcome rising drug development costs, reduce out-of-pocket expenses for patients, and, as a result, lower the real cost of therapy, which is why drug repurposing is widely regarded as a promising area in drug development. *https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/repurposing
The aim is to reduce approval times and improve the success of clinical development, considering the therapeutic challenges of malignant diseases, the economic impact on health systems, and the unmet needs of patients.
Repurposing of drugs can be accomplished either experimentally (activity-based) or computationally. One disadvantage of the experimental approach is the need to develop a screening test and to collect a large number of drug molecules for testing, which can lead to significant time and labor costs. Computational drug repurposing, on the other hand, is considered a faster approach because it uses bioinformatics tools and databases of drug-related data to identify candidate drugs for repurposing (Shim & Liu, 2014).
Growing evidence indeed suggests that any functional compound classified as safe for human use is likely to have multiple therapeutic applications.
To circumvent some of the most expensive drug discovery processes, companies pursue this strategy to increase their productivity (new drugs to market) by reducing the discovery and development timeline. This decreases the overall cost of bringing the drug to market because the safety and pharmacokinetic profiles of the repositioned candidates are already established. *https://www.sciencedirect.com/topics/medicine-and-dentistry/drug-repositioning
The economic and social burden of cancer is enormous, so measures must be taken to relieve this burden and to ensure continued access to therapies for all patients. This review focuses on how conventional therapies against breast cancer are leading to resistance, by reviewing those mechanisms and discussing the efficacy of repurposed drugs to fight breast cancer.
Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division. In molecular biology, "tubulin" can refer either to the tubulin protein superfamily of globular proteins or to one of its member proteins. Tubulins are targets for anticancer drugs such as vinblastine a
nd vincristine, and paclitaxel. The anti-worm drugs mebendazole and albendazole, as well as the anti-gout agent colchicine, bind to tubulin and inhibit microtubule formation.
While the former ultimately lead to cell death in worms, the latter arrests neutrophil motility and decreases inflammation in humans. The antifungal drug griseofulvin targets microtubule formation and has applications in cancer treatment.
*Costa, B., Amorim, I., Gärtner, F., & Vale, N. (2020). Understanding Breast cancer: From conventional therapies to repurposed drugs. European Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.ejps.2020.105401
*van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R (March 2004). “The Catharanthus alkaloids: pharmacognosy and biotechnology”. Current Medicinal Chemistry. 11 (5): 607–28. doi:10.2174/0929867043455846. PMID 15032608.
*Raviña, Enrique (2011). “Vinca alkaloids”. The evolution of drug discovery: From traditional medicines to modern drugs. John Wiley & Sons. pp. 157–159. ISBN.
*Cooper, Raymond; Deakin, Jeffrey John (2016). “Africa’s gift to the world”. Botanical Miracles: Chemistry of Plants That Changed the World. CRC Press. pp. 46–51. ISBN.
Benzimidazoles such as mebendazole and fenbendazole disrupt the tiny structures (microtubules) inside types of cancer cells. Because cancer cells deteriorate and can’t maintain their internal structure, they die. Benzimidazoles inhibit microtubule dynamics, which can slow or stop cancer’s progression. Research has shown changes in cancer cells, reduced tumor growth, and potential synergy with other well-known, approved cancer treatments.
Fenbendazole is generally sold as oral granules or as a liquid suspension and is given by mouth.
The benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. They also have limited activity against cestodes.
Anthelmintics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by stunning or killing them, without causing significant damage to the host.
Anthelmintic Agents
Anthelmintic agents available in the United States [with year of approval] include the benzimidazoles (thiabendazole [1967], mebendazole [1974], albendazole [1996], and triclabendazole [2019]), ivermectin [1996], nitazoxanide [2004], praziquantel [1982], pyrantel pamoate, and niclosamide [not available in the United States]. Their mechanisms of action vary, but they frequently cause paralysis of the parasitic worm, leading to its release and expulsion.
*LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Anthelmintic Agents. [Updated 2021 Sep 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548602/
Mebendazole (methyl 5-benzoyl-1H-benzimidazol-2-yl-carbamate) was introduced in 1968 as a broad-spectrum anthelmintic and was first applied to human subjects in 1971.
*Meco, D., Mastrangelo, S., Navarra, P., & Ruggiero, A. (2023). Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers. https://doi.org/10.3390/ijms24021334
When Fenbendazole is metabolized by the liver, it is converted into its active metabolite, oxfendazole. This outcome enhances its anthelmintic effect.
Fenbendazole has been used for decades in animal treatment. It is a broad-spectrum benzimidazole anthelmintic used against gastrointestinal parasites including Giardia, roundworms, hookworms, whipworms, the tapeworm genus Taenia, pinworms, Aelurostrongylus, paragonimiasis, strongyles, and strongyloidiasis, and can be administered to sheep, cattle, horses, fish, dogs, cats, rabbits, most reptiles, freshwater shrimp tanks as planaria and hydra treatments, as well as seals.
The human equivalent of Fenbendazole is Mebendazole, which is FDA-approved for the treatment of parasitic infections in people but not for cancer.
Since fenbendazole is not currently approved by the FDA or EMA, its pharmacokinetics and safety in humans have yet to be well documented in the medical literature. Despite this, insights can be drawn from existing in vitro and in vivo animal studies on its pharmacokinetics. Given the low cost of fenbendazole, its high safety profile, accessibility, and unique anti-proliferative activities, fenbendazole would be the preferred benzimidazole compound to treat cancer.
*Oral Fenbendazole for Cancer Therapy in Humans and Animals https://ar.iiarjournals.org/content/anticanres/44/9/3725.full.pdf
The process of repurposing veterinary drugs that show promising results for human use involves applying medications initially developed for animals to treat human conditions. This can reduce the time and costs required to develop new drugs. Fenbendazole, for example, has a wide safety margin and is well tolerated in most species, with very low toxicity and a high safety profile in experimental animals.
First introduced in 1974, Fenbendazole is now distributed worldwide. Building on its established safety in animals, Fenbendazole, like many chemotherapy drugs, can also kill cancer cells but with lower toxicity and fewer adverse effects for patients.