Microtubule Targeting Agents in Cancer Therapy: Elucidating the Underlying Molecular Mechanisms

Abstract

Microtubules are intracellular components of cytoskeleton throughout the cytoplasm of all eukaryotic cells. Microtubules are dynamic polymers with continuous assembly and disassembly of tubulin dimers. This highly dynamic action of microtubule contributes to numerous cellular processes such as maintaining the structure of the cell, cell division and cell movement. For this reason, microtubule has become a notable target for chemotherapeutic achievements. Microtubule Targeting Agents (MTAs) that nowadays are used in chemotherapy, induce microtubule polymerization or depolymerization. They are categorized into two groups known as stabilizers such as texanes and destabilizers such as vincas. Either, stabilizing or destabilizing of microtubule polymer leads to spindle assembly poisoning, mitotic blockage and cell death. Yet, we are required to consider main forthcoming controversial difficulty which is resistance to MTAs. Clinical studies have documented different levels of resistance to MTAs with different durability among patients even within the same class of drugs. For instance, overexpression of P-glycoprotein (P-gp) is linked to resistance to taxanes, but not to ixabepilone, even though they have similar mechanism of action. Mutations in β-tubulin have been associated with resistance to taxanes but not to epithilones despite their mechanism of action being same. Also, there is association between poor response to taxanes and overexpression of βIII-tubulin. Either receiving benefit or harm from MTAs, depends on each individual patient considering their variable chemo-sensitivities to drugs. Therefore, it is crucial to understand the basic biology of microtubules and the molecular mechanisms by which MTAs exert their activity. This is especially important considering their current application in cancer therapy. In this chapter we discussed about MTAs in detail and illustrate their molecular mechanisms involved in various cancers.