Repurposing old drugs to fight multidrug resistant cancers

Abstract

Overcoming multidrug resistance represents a major challenge for cancer treatment.In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore-and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, proapoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…Other repurposed drugs that have been reported to be active in BC because of their pHi-related acidifying effects are quercetin, resveratrol, phloretin, lonidamine, niclosamide, docosahexaenoic acid (DHA), simvastatin and the K + ionophore salinomycin [ 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 ]. These and other repurposed drugs for cancer have been recently reviewed and proposed to show antiproliferative, pro-apoptotic and/or antimetastatic activity [ 304 ], either in BC or other tumors.…”

Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors

“…Although P-gp inhibitors showed high efficacy in vitro and in vivo studies, very few have successfully passed all phases of the clinical trials and none of them have been approved by the U.S. Food and Drug Administration (FDA) for clinical use in cancer treatment ( Nanayakkara et al, 2018 ; Robinson and Tiriveedhi, 2020 ). After three generations of P-gp inhibitors, a fourth generation comprised of nature-originated compounds has emerged ( Dinić et al, 2020 ). Therefore, identification of natural compounds that can exert anticancer effects and at the same time revert the MDR contributes to the efforts of the cancer research community to combat this multifactorial disease.…”

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

“…Interestingly, the recent development and increasing interest observed in genomic and proteomic technologies for the assessment of cancer specific biological pathways has led to the discovery of several new drug targets, providing excellent opportunities for drug repurposing, since almost every drug used in human therapy has the potential to address more than one target [3]. The increasing interest in this approach relies on the fact that, by finding new applications for clinically approved drugs, drug repurposing is able to overcome the major issues associated with conventional drug discovery, which include substantial costs, slow pace and high risk of failure [3,4]. According to Nosengo (2016), the estimated cost for a repurposed drug to reach the market is US$300 million, whereas, for a new drug, it is estimated to be~$2 to $3 ~$2 to $3 billion [5].…”

“…Therefore, the need for large investments and the time frame for drug development can be significantly reduced [1,3]. As depicted in Figure 1, while new drug discovery and development might take up to 10 to 17 years for a drug to reach the market, the timeline for drug repurposing is only about 3 to 12 years [4]. Additionally, the previous evidence on the effect of these drugs in preclinical models and in humans reduces the risk of failure in upcoming clinical trials [1].…”