Tubulin: a target for antineoplastic drugs into the cancer cells but also in the peripheral nervous system

Abstract

Since the introduction into clinical practice of vinca alkaloids, tubulin has become a key and well-established target of modern antineoplastic chemotherapy. When taxanes became available their broad spectrum of activity was striking and opened up new horizons for cancer patients' treatment. However, taxanes' susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein, is not infrequent and their use may be limited by poor solubility, synthetic problems and toxicity. The epothilones are a new class of chemotherapeutic agents with a mechanism of action similar to that of taxanes, but different enough to escape, for example, the multidrug resistance caused by P-glycoprotein. Moreover, the epothilones (that are strong promoters of tubulin polymerization) have significant antitumor activity against human cancer cells that are taxane-resistant, express the multidrug resistance gene MDR-1, and have acquired tubulin mutations. Finally, starting from the natural molecules, several synthetic analogues have been developed. Besides their antineoplastic efficacy, all the antitubulin drugs share a common toxicity on the peripheral nervous system and peripheral neurotoxicity is a major, potentially dose-limiting side effect also of the epothilones. The current knowledge regarding the features of epothilones' peripheral neurotoxicity and their comparison with taxanes will be reviewed.