Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes

Abstract

Taxanes represent one of the most promising classes of anticancer agents. Unfortunately, their clinical success has been limited by the insurgence of cellular resistance, mainly mediated by the expression of the MDR phenotype or by microtubule alterations. However, the remarkable relevance of paclitaxel and docetaxel in clinical oncology stimulated intensive efforts in the last decade to identify new derivatives endowed with improved activities towards resistant tumor cells, resulting in a huge number of novel natural and synthetic taxanes. Among them, several structurally different derivatives were found to exhibit a promising behavior against the MDR phenotype in terms of either MDR inhibiting properties, or enhanced cytotoxicity compared to parental drugs, or both. On the other hand, only in more recent years have the first taxanes retaining activity against resistant cancer cells bearing alterations of the tubulin/microtubule system emerged. This review describes the main molecular mechanisms of resistance to paclitaxel and docetaxel identified so far, focusing on the advances achieved in the development of new taxanes potentially useful for the treatment of resistant tumors.