From farm to clinic? Exploring the anticancer potential of monensin and its semisynthetic derivatives

Natural products have traditionally played a pivotal role in the field of drug discovery, offering chemists and biologists an abundant source of inspiration regarding a variety of structures and functions. Notably, the identification of anticancer activities in several renowned antibiotics over the past years has opened new therapeutic avenues and highlighted the significance of drug repurposing strategies. In this context, we provide a comprehensive review of monensin (MON), a natural polyether ionophore antibiotic, delineating its biological and chemical properties and summarizing various approaches, particularly structural modifications, employed to explore its potential in cancer-related research. Preclinical investigations have demonstrated that MON effectively targets a wide range of cancer cells, including those exhibiting stem cell-like properties. Its combination with standard chemotherapeutics appears especially promising in this context. While nanotechnology may help address some clinical limitations of MON, extensive research over the past decade has focused on the derivatization of its most reactive functional groups, such as C1 carboxyl and C26 hydroxyl, to produce semisynthetic derivatives with improved anticancer activity compared to the native structure. We hope that the findings presented in this review will inspire and motivate researchers to initiate, sustain, and broaden studies of the off-label use of MON in the ongoing battle against cancer.