Mechanisms of Taxol resistance related to microtubules

Abstract

Since its approval by the FDA in 1992 for the treatment of ovarian cancer, the use of Taxol has dramatically increased. Although treatment with Taxol has led to improvement in the duration and quality of life for some cancer patients, the majority eventually develop progressive disease after initially responding to Taxol treatment. Drug resistance represents a major obstacle to improving the overall response and survival of cancer patients. This review focuses on mechanisms of Taxol resistance that occur directly at the microtubule, such as mutations, tubulin isotype selection and post-translational modifications, and also at the level of regulatory proteins. A review of tubulin structure, microtubule dynamics, the mechanism of action of Taxol and its binding site on the microtubule are included, so that the reader can evaluate Taxol resistance in context.

Figure 1

Structures of microtubule-stabilizing agents

Figure 2

Three-dimensional model of α/β-tubulin heterodimer. Domains of β-tubulin that are discussed in the text, as well as the stabilizing loop (S-loop) unique to α-tubulin, are colored in red. Helix 3 (H3) and microtubule loop (M-loop) in α-tubulin are labeled in blue. Amino-acid residues close to Taxol are indicated in gray

Figure 3

Primary sequences and secondary structure of the major human α- and β-tubulin isotypes. Helices (H1–H12) are represented as red rectangles and β-sheets (S1–S10) are represented as blue arrows. Mutations detected in Taxol-resistant cell lines are highlighted in black