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.
Biomed Pharmacother. 2024 Nov;180:117554. doi: 10.1016/j.biopha.2024.117554. Epub 2024 Oct 15.
Chemotherapy treatment faces a major obstacle with the emergence of multidrug resistance (MDR), often attributed to the elevated expression of ATP-binding cassette (ABC) transporters such as ABCG2 and ABCB1 in cancer cells. These transporters hinder the efficacy of cytotoxic drugs via ATP hydrolysis-dependent efflux, leading to diminished intracellular drug levels. The scarcity of approved treatments for multidrug resistant cancers necessitates exploration of alternative strategies, including drug repositioning of molecular targeted agents to counteract ABCG2-mediated MDR in multidrug-resistant cancer cells. This study investigates the potential of edicotinib, a selective colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase inhibitor that is currently undergoing clinical trials for various diseases, to reverse MDR in ABCG2-overexpressing cancer cells. Our findings reveal that by attenuating the drug-efflux function of ABCG2 without altering its expression, edicotinib improves drug-induced apoptosis and reverses MDR in ABCG2-overexpressing multidrug-resistant cancer cells at non-toxic concentrations. Through ATPase activity analysis and molecular docking, potential interaction sites for edicotinib on ABCG2 were identified. These results underscore an additional pharmacological benefit of edicotinib against ABCG2 activity, suggesting its potential incorporation into combination therapies for patients with ABCG2-overexpressing tumors. Further research is warranted to validate these findings and explore their clinical implications.
化疗治疗面临着一个主要的障碍，即多药耐药（MDR）的出现，这通常归因于癌细胞中 ATP 结合盒（ABC）转运蛋白的高表达，如 ABCG2 和 ABCB1。这些转运蛋白通过 ATP 水解依赖性外排来阻碍细胞毒性药物的疗效，导致细胞内药物水平降低。缺乏批准用于多药耐药癌症的治疗方法，需要探索替代策略，包括将分子靶向药物重新定位，以对抗多药耐药癌细胞中 ABCG2 介导的 MDR。本研究探讨了 edicotinib 的潜力，edicotinib 是一种选择性集落刺激因子-1 受体（CSF-1R）酪氨酸激酶抑制剂，目前正在各种疾病的临床试验中进行研究，以逆转 ABCG2 过表达的癌细胞中的 MDR。我们的研究结果表明，edicotinib 通过减弱 ABCG2 的药物外排功能而不改变其表达水平，在非毒性浓度下改善了 ABCG2 过表达的多药耐药癌细胞中药物诱导的细胞凋亡并逆转了 MDR。通过 ATPase 活性分析和分子对接，确定了 edicotinib 在 ABCG2 上的潜在相互作用位点。这些结果强调了 edicotinib 对 ABCG2 活性的额外药理学益处，表明其可能被纳入 ABCG2 过表达肿瘤患者的联合治疗中。需要进一步的研究来验证这些发现并探讨其临床意义。
