Clotrimazole as a new frontier: Drug repurposing and its efficacy in cancer therapy

Cancer, ranging from early stages to metastatic spread, is one of the leading causes of death globally. Current treatment options, including chemotherapy, radiotherapy, and targeted drugs, have limitations, such as significant side effects, drug resistance, and high cost. To overcome these challenges, extensive studies have explored the anticancer potential of various drugs such as clotrimazole (CLZ), which has shown promising anticancer effects. CLZ was first developed as an antifungal agent. Recently significant anticancer effects have been observed making it a suitable candidate for drug repurposing. Compared with other azole-based antifungals, CLZ has shown distinct therapeutic effects on cancer cells via several pathways. Its ability to disrupt glycolysis by inhibiting phosphofructokinase (PFK) and hexokinase (HK) distinguishes it from other azoles. Furthermore, CLZ obstructs calcium homeostasis and critical survival pathways, such as extracellular signal-regulated kinase (ERK)-p65, phosphatidylinositol 3-kinase (PI3K), and mitochondrial apoptotic pathways, inhibiting tumor growth, inducing apoptosis, and attenuating metastasis. This review explores the potential of repurposing CLZ in cancer and its well-established safety profile and cost-effectiveness to highlight current treatment gaps. It briefly examines in vitro and in vivo assessments to understand the mechanisms and effects of CLZ on various cancer types. Furthermore, novel strategies such as nanoformulations and combination therapies with existing chemotherapeutic drugs have been highlighted to improve therapeutic outcomes. Preclinical studies have provided promising evidence for the efficacy of CLZ in different cancers, showing tumor regression and improved responses to conventional chemotherapy or targeted therapies. Given its evident preclinical results and diverse mechanisms of action, CLZ may be considered an antineoplastic agent. Further clinical research is required to fully elucidate its anticancer potential, potentially positing it as a valuable addition to currently available cancer treatments.