Taxol®: The First Microtubule Stabilizing Agent.

Chia-Ping Yang,Susan Horwitz

doi:10.3390/ijms18081733

Abstract

Taxol®, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol® emphasizes the research done in the Horwitz’ laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol® toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol® is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol®.

Highlights

Introduction® (Figure 1), a diterpenoid of natural product origin, TheThe stabilization stabilization of of microtubules microtubules by by Taxol Taxol® (Figure1), a diterpenoid of natural product origin, was was first first described described in in an an in in vitro vitro microtubule microtubule assembly assembly assay assay in in the the late late 1970s 1970s [1][1] and and aa year year later later in in mouse fibroblast cells [2].This represented a novel mechanism of action for a small molecule with the mouse fibroblast cells [2]
These include: (1) The Taxol® -resistant human lung carcinoma cell line A549.T12 that contains an α-tubulin mutation at residue 379 that is near the C-terminus, a site of interaction with microtubule associated proteins
The mutations found in microtubule-stabilizing agents (MSAs)-resistant cell lines have not been detected in human tumors following chemotherapy; they provide information that allow us to further understand the structure of tubulin, effects of drugs on microtubule dynamics, and the mechanisms involved in drug resistance and dependence

Summary

Introduction

1), a diterpenoid of natural product origin, was was first first described described in in an an in in vitro vitro microtubule microtubule assembly assembly assay assay in in the the late late 1970s. [1] and and aa year year later later in in mouse fibroblast cells [2]. This represented a novel mechanism of action for a small molecule with the mouse fibroblast cells [2]. This represented a novel mechanism of action for a small molecule with potential to betoan antitumor agent. ThisThis short review highlights the contributions of the the potential beimportant an important antitumor agent. Taxol the Horwitz’ Laboratory to our understanding of the mechanism of action of Taxol

Structure

Drug Resistance

Photolabeling

Insights into the Stabilization of Microtubules by Taxol

Conclusions