Editorial: Repurposed Drugs Targeting Cancer Signaling Pathways: Dissecting New Mechanism of Action Through In Vitro and In Vivo Analyses.

Abstract

In today’s fast-paced society, efficiency is critical in many aspects, especially in costly, resource-intensive processes such as drug discovery and development. Technological advances that expedite chemical compound synthesis or allow for parallel processing of multiple samples can only do so much to reduce the time it takes for a new drug discovered in a lab bench to reach the pharmacy aisles, mainly due to strict safety requirements that a particular drug can take years to fulfill. Enter drug repurposing, a clever strategy to reduce overall development time and cost by employing drugs already on the market –already deemed safe for consumption– and applying them to treat a disease other than it was initially approved for (1). This strategy has successfully led to the discovery of new roles for different compounds such as antibiotics (2) or analgesics (3), and is currently employed in the search for novel treatments for a wide range of conditions, from autoimmune diseases (4) to asthma (5), and even COVID-19 (6). Naturally, drug repurposing as alternative cancer therapies has become an active research area. Local and non-metastatic cancers are primarily treated with surgery and radiotherapy, while chemotherapy, hormone, and targeted therapies are currently used for advanced cases (7). However, novel treatment alternatives are needed to tackle the resistance that cancer cells develop against these drugs, while maintaining development costs under control; repurposed drugs fit the bill perfectly. To size up research on drug repurposing, Baker and colleagues reviewed the literature relevant to drug development and found that by 2018 over 60% of the drugs used have been tested for repurposing (8). Nonetheless, reports on the efficiency of drug repurposing show success rates around 5-10% (9). This less-than-ideal efficiency calls for a switch from serendipity to purposeful analysis when searching for new repositioning candidates. Common molecular signaling pathways contributing to the development of cancer and other diseases or conserved among different cancer types are the most conspicuous targets for drug repurposing. For instance, cyclin-dependent kinases (CDKs) exert their function in cell cycle control (10) and transcriptional regulation (11). These molecules can be targeted with anti-cancer (12) and anti-viral (13) drugs. Several groups are investigating common molecular signaling pathways in diverse cancer types, with the common goal of repurposing drugs that have been used for other diseases. Signaling pathways are not only common to various cancers; these are shared between cancer and other seemingly unrelated diseases. This Research Topic compiled research that described drugs from all walks of pharmacology –from natural products to custom-designed molecules– that are being repositioned. Among these, in-silico docking analysis combined with cell and biochemical experiments demonstrated that the antifungal tioconazole can inhibit the autophagy-related protein ATG4, which decreased the viability of colorectal and breast cancer cells (14). Autophagy was further targeted by drugs originally used to treat diverse diseases such as malaria and type-2 diabetes ( Figure 1 ). In this regard, chloroquine and mefloquine were originally approved as therapies against malaria, however these drugs have anticancer effects through the regulation of autophagy, as Eloranta et al. and Xie et al. demonstrated in hepatoblastoma and esophageal squamous cell carcinoma, respectively. In addition, Coronel-Hernandez and collaborators combined the autophagy-regulating properties of metformin, initially approved for type 2 diabetes, and the metabolic regulation exerted by sodium oxamate with the anti-proliferating activity of a tested chemotherapy agent to achieve a synergistic effect in colorectal cancer. Finally, Xu et al. showed that the leprosy treatment clofazimine inhibits Wnt signaling impairing the growth of colorectal cancer, hepatocellular carcinoma, ovarian cancer, and glioblastoma. Open in a separate window Figure 1 Inhibition of autophagy was a prevalent subject matter in the papers submitted to this research topic. Drugs with this effect, such as Metformin and Chloroquine, can be repurposed from malaria and type-2 diabetes to treat colorectal cancer, hepatoblastoma, and esophageal squamous cell carcinoma. Background arrows indicate the direction of drug repurposing.