The roles of beta-tubulin mutations and isotype expression in acquired drug resistance.

Article Details

Citation

Huzil JT, Chen K, Kurgan L, Tuszynski JA

The roles of beta-tubulin mutations and isotype expression in acquired drug resistance.

Cancer Inform. 2007 Apr 27;3:159-81.

PubMed ID
19455242 [ View in PubMed
]
Abstract

The antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the alpha/beta-tubulin heterodimer, GTP becomes bound to both the alpha and beta-tubulin monomers. During microtubule assembly, the GTP bound to beta-tubulin is hydrolyzed to GDP, eventually reaching steady-state equilibrium between free tubulin dimers and those polymerized into microtubules. Tubulin-binding drugs such as paclitaxel interact with beta-tubulin, resulting in the disruption of this equilibrium. In spite of several crystal structures of tubulin, there is little biochemical insight into the mechanism by which anti-tubulin drugs target microtubules and alter their normal behavior. The mechanism of drug action is further complicated, as the description of altered beta-tubulin isotype expression and/or mutations in tubulin genes may lead to drug resistance as has been described in the literature. Because of the relationship between beta-tubulin isotype expression and mutations within beta-tubulin, both leading to resistance, we examined the properties of altered residues within the taxane, colchicine and Vinca binding sites. The amount of data now available, allows us to investigate common patterns that lead to microtubule disruption and may provide a guide to the rational design of novel compounds that can inhibit microtubule dynamics for specific tubulin isotypes or, indeed resistant cell lines. Because of the vast amount of data published to date, we will only provide a broad overview of the mutational results and how these correlate with differences between tubulin isotypes. We also note that clinical studies describe a number of predictive factors for the response to anti-tubulin drugs and attempt to develop an understanding of the features within tubulin that may help explain how they may affect both microtubule assembly and stability.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
VinflunineTubulin beta chainProteinHumans
Yes
Inhibitor
Details