Li Yen-Ching, Lin Bing-Huan, Murakami Megumi, Wu Yu-Shan, Hung Tai-Ho, Chen Chin-Chuan, Ambudkar Suresh V, Wu Chung-Pu
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan.
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Eur J Pharmacol. 2025 Feb 5;988:177231. doi: 10.1016/j.ejphar.2024.177231. Epub 2024 Dec 24.
Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.
多药耐药性（MDR）仍然是癌症治疗中的一个重大障碍，主要归因于癌细胞内ATP结合盒（ABC）转运蛋白如ABCB1和ABCG2的过表达。这些转运蛋白通过促进ATP水解依赖性药物外排，积极降低细胞毒性药物的有效性，从而减少细胞内药物积累。鉴于目前尚无针对多药耐药性癌症的获批治疗方法，以及酪氨酸激酶抑制剂（TKIs）与传统抗癌药物联合使用已证实的益处，我们研究了目前正在进行临床试验的强效c-Abl TKI沃多替尼在恢复对过表达ABCB1和ABCG2的多药耐药癌细胞对化疗药物敏感性方面的潜力。结果表明，以亚毒性浓度给药的沃多替尼以浓度依赖性方式有效恢复多药耐药癌细胞对细胞毒性药物的敏感性。此外，沃多替尼通过抑制ABCB1和ABCG2的药物外排功能，同时维持其表达水平，增强了这些细胞中药物诱导的凋亡。此外，我们发现，虽然沃多替尼增强了ABCB1和ABCG2的ATP酶活性，但这些转运蛋白的过表达并未诱导对沃多替尼的耐药性。这些结果强烈表明，ABCB1或ABCG2水平的升高不太可能在癌症患者对沃多替尼的耐药性发展中起重要作用。总体而言，我们的研究结果揭示了沃多替尼针对ABCB1和ABCG2活性的另一个药理学方面，表明其有可能纳入针对特定亚组具有高ABCB1或ABCG2水平肿瘤患者的联合治疗中。有必要进行进一步研究以充分阐明这种治疗方法的临床意义。
