Resistance to anti-tubulin agents: From vinca alkaloids to epothilones.

Werner Krause

doi:10.20517/cdr.2019.06

Abstract

This review describes the mechanism of action - inhibition of microtubules - and the most important mechanisms of resistance for vinca alkaloids, taxanes and epothilones. Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target, the microtubules, by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs. In some cases, however, this process can have the opposite effect, leading to sensitization, e.g., for vinca alkaloids in cases where taxanes are not or no longer effective. The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered. Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis, post-translational modifications of microtubules and other protein pathways, micro-RNAs, induction of oncogenes, and cancer stem cells, which, taken together, offer particularly multifold possibilities for preventing drug activity. The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.

Highlights

Anti-tubulin agents (ATAs) represent a class of anti-cancer drugs that are targeting one of the most fundamental processes in the organism, mitosis and cell division[1]
This review describes the mechanism of action - inhibition of microtubules - and the most important mechanisms of resistance for vinca alkaloids, taxanes and epothilones
Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target, the microtubules, by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs

Summary

INTRODUCTION

Anti-tubulin agents (ATAs) represent a class of anti-cancer drugs that are targeting one of the most fundamental processes in the organism, mitosis and cell division[1]. Overexpression of P-gp, encoded by the MDR1 gene, decreases intracellular drug levels, limiting drug cytotoxicity It is the most common mechanism involved in the development of resistance associated with poor response to microtubule-targeted agents including taxanes and vinca alkaloids and subsequent treatment failure[93,94]. Knockdown of ZEB1, an EMT transcription factor, in human breast cancer cells reduced β-tubulin isotype classes I, III, and IVB mRNA, whereas upregulation of ZEB1 was associated with increases in these isotype classes Another line of defense against cytotoxic drugs includes regulatory proteins, in particular alterations to tubulin through PTMs that affect regulatory protein binding, and altered expression or PTMs to tubulin-/ microtubule-regulatory proteins[51].

Summary and outlook

Findings

CONCLUSION