Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired

Abstract

Taxanes and anthracyclines are two of the most potent and broadly effective classes of chemotherapeutic agents. However, resistance to these agents is common and significantly limits their potential. As such, there is a great need to understand the mechanisms underlying de novo and acquired resistance to these agents. Beyond the resistance barrier lies even greater potential to significantly alter the natural course of human cancer. This review discusses what we currently understand about the mechanisms of resistance to taxanes and anthracyclines. Preclinical models suggest a role for ATP-binding cassette transporters, tubulin isoforms, microtubule-associated proteins, tubulin gene mutations, and mitotic checkpoint signaling proteins in resistance to taxanes. Preclinical models also suggest that drug transport proteins, antioxidant defenses, apoptotic signaling, and topoisomerase modulation may mediate anthracycline resistance. Many of these hypotheses remain untested in appropriately designed clinical studies, but limited clinical evidence will be reviewed. Epothilones represent a novel class of non-taxane microtubule stabilizing agents with distinct drug-resistance profiles. Potential mechanisms behind these differences and their potential role in the treatment of both taxane- and anthracycline-refractory patients are discussed.