DTA0100, dual topoisomerase II and microtubule inhibitor, evades paclitaxel resistance in P-glycoprotein overexpressing cancer cells

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Ana Podolski-RenićMilica Pešić

Abstract

The efficacy of microtubule targeting agents in cancer treatment has been compromised by the development of drug resistance that may involve both, P-glycoprotein overexpression and the changes in β-tubulin isoforms' expression. The anti-Topoisomerase II activity of methyl 4-((E)-2-(methoxycarbonyl)vinyloxy)oct-2-ynoate (DTA0100) was recently reported. Herein, we further evaluated this propargylic enol ether derivative and found that it exerts inhibitory effect on tubulin polymerization by binding to colchicine binding site. DTA0100 mitotic arrest properties were investigated in two multi-drug resistant cancer cell lines with P-glycoprotein overexpression (colorectal carcinoma and glioblastoma). The sensitivity of multi-drug resistant cancer cell lines to DTA0100 was not significantly changed in contrast to microtubule targeting agents such as paclitaxel, vinblastine and colchicine. DTA0100 clearly induced microtubule depolymerization, leading to disturbance of cell cycle kinetics and subsequent apoptosis. The fine-tuning in β-tubulin isoforms expression observed in multi-drug resistant cancer cells may influence the efficacy of DTA0100. Importantly, DTA0100 blocked the P-glycoprotein function in both multi-drug resistant cancer...Continue Reading

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Citations

Jun 8, 2018·Current Medicinal Chemistry·Tijana StankovićMilica Pešić
Jun 10, 2019·Investigational New Drugs·Jelena DinićJosé M Padrón
Jan 19, 2019·Anti-cancer Agents in Medicinal Chemistry·Harbinder SinghSahil Sharma
Feb 23, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Sabrina DallavalleRoberta Fruttero
Mar 11, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Tuyelee DasAbhijit Dey
Jun 9, 2021·Journal of Medicinal Chemistry·Wen ShuaiYuxi Wang
Oct 9, 2019·Journal of Medicinal Chemistry·Žiga SkokJanez Ilaš

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