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

• Published in: Apoptosis (London) 2022-12, Vol.27 (11-12), p.1015-1030
• Main Authors: Jia, Lina, Gao, Xiaoyun, Fang, Yi, Zhang, Haotian, Wang, Lihui, Tang, Xing, Yang, Jingyu, Wu, Chunfu
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Care and treatment; Cell Biology; Cell cycle; Cisplatin; Cytotoxicity; Drug resistance; Drug resistance in microorganisms; Effectiveness; Efflux; Glycoproteins; In vivo methods and tests; Lung cancer; Lung cancer, Non-small cell; Lung carcinoma; Micelles; Multidrug resistance; Non-small cell lung carcinoma; Oncology; P-Glycoprotein; Paclitaxel; Polymerization; Small cell lung carcinoma; Taxanes; Tubulin; Tubulins; Vincristine; Virology; Xenografts; Xenotransplantation
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-022-01767-4

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 IC 50 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 G 2 -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.