High expression of class III β-tubulin has no impact on functional cancer cell growth inhibition of a series of key vinblastine analogs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Boger, Dale L.¹ 

[1] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

关键词: Vinblastine;    Vinca alkaloids;    Class III beta-tubulin;    Drug resistance;   

DOI  :  10.1016/j.bmcl.2018.02.006

来源: Elsevier

【 摘 要 】

Clinical association studies have implicated high expression of class III beta-tubulin as a predictive factor for lower response rates and reduced overall survival in patients receiving tubulin binding drugs, most notably the taxanes. Because of the implications, we examined a series of key vinblastine analogs that emerged from our studies in functional cell growth inhibition assays for their sensitivity to high expression of class III beta-tubulin (human non-small cell lung cancer cell line A549 vs taxol-resistant A549-T24). Unlike taxol, vinblastine and a set of key analogs 3-10 did not exhibit any loss in sensitivity toward A549-T24. The results suggest that vinblastine and related analogs are not likely prone to resistance derived from high expression of class III beta-tubulin unlike the taxanes. Most significant are the results with 4-6, a subset of 200 amide vinblastine analogs. They match or exceed the potency of vinblastine and they display more potent activity against taxol-resistant A549-T24 than even wild type A549 cells (1.2-2-fold), complementing our prior observations that they also display no sensitivity to overexpression of Pgp (HCT116/VM46 vs HCT116) and are not subject to resistance derived from Pgp efflux. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

Free