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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 5; pp. 863 - 865
• Main Authors: Radakovic, Aleksandar, Boger, Dale L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2018
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Cell Proliferation - drug effects; Class III β-tubulin; Dose-Response Relationship, Drug; Drug resistance; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Tubulin - biosynthesis; Vinblastine; Vinblastine - chemistry; Vinblastine - pharmacology; Vinca alkaloids; Vinblastine; Vinca alkaloids; Class III β-tubulin; Drug resistance
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2018.02.006

[Display omitted] Clinical association studies have implicated high expression of class III β-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 β-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 β-tubulin unlike the taxanes. Most significant are the results with 4–6, a subset of 20′ 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.