TM2, a novel semi-synthetic taxoid, exerts anti-MDR activity in NSCLC by inhibiting P-gp function and stabilizing microtubule polymerization.

ABSTRACT

Taxane agents are of particular interest in non-small cell lung carcinomas (NSCLC) treatment, while multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) limits their clinical efficacy. TM2, a chemically semi-synthesized taxane derivative, exerted significant anti-cancer efficacy in vitro and in vivo, especially against vincristine-resistant and adriamycin-resistant cancer cells. In this study, the anti-cancer effect of TM2 on drug-resistant NSCLC was evaluated both in vitro and in vivo, and the mechanism underlying its anti-MDR activity was further clarified. It was found that TM2 was significantly cytotoxic to cisplatin- and paclitaxel-resistant A549 (human non-small cell lung cancer) cells that overexpressing P-gp, resulting in IC50 values of 0.19 µM and 0.12 µM. TM2 micelles (5 mg/kg, 10 mg/kg, 20 mg/kg, i.v., 21 days) inhibited the growth of MDR xenograft with the maximal inhibitory rate up to 80.4%. Moreover, TM2 caused cell cycle arrest in the G2-M phase and apoptosis in drug-resistant cells through promoting tubulin polymerization, which acted in a way similar to taxane agents. Notably, TM2 acted as a P-gp inhibitor with high binding affinity, which resulted in impaired efflux function through forming H-bonds and ATP hydrolysis to induce P-gp conformational alterations. These findings indicated that TM2 displays anti-MDR activity with the potential for the treatment of NSCLC, which can inhibit P-gp function and stabilize microtubule polymerization.