Resistance of prostate cancer to topoisomerase inhibitors

Prostate cancer is a leading cause of cancer-related mortality in men. Chemotherapy with topoisomerase inhibitors, such as etoposide and mitoxantrone, has been used in the past in the setting of advanced prostate cancer refractory to prior lines of treatment. However, resistance to topoisomerase inhibitors is a clinical problem that limits their efficacy in the treatment of prostate cancer. DNA topoisomerases are enzymes that play a crucial role in DNA topology regulation and genomic stability. These enzymes act through the induction of transient DNA-strand breaks, allowing the passage of intact DNA strands through the broken strands. Topoisomerases have emerged as attractive targets for the development of anticancer. Topoisomerase inhibitors are a class of chemotherapeutic agents that target these enzymes by interfering with their catalytic activity. These inhibitors can be classified into two main categories: topoisomerase I inhibitors and topoisomerase II inhibitors. Mechanisms of resistance to topoisomerase inhibitors can be thought of through distinct categories based on their relation to cleavage complex formation. Precleavage complex mechanisms involve drug metabolism and uptake, which ultimately prevent the formation of the cleavage complex. ATP-binding cassette transporters, such as ABCC4 and ABCG4, actively remove topoisomerase inhibitors from cells, thereby reducing their intracellular concentration and efficacy. Modifications of the topoisomerase enzyme itself via an acquired mutation in the core subdomain I of topoisomerase I reduce the number of cleavage complexes formed. Postcleavage complex mechanisms allow for modification in pathways related to cell cycle regulation and apoptosis for the sake of cellular survival in the cytotoxic environment created by topoisomerase inhibitors.