Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Department of Histology and Embryology, Weifang Medical University, Weifang 261053, China.
Int J Mol Sci. 2019 Jan 11;20(2):268. doi: 10.3390/ijms20020268.
ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration of chemotherapeutic drugs. Here, we evaluated ciprofloxacin for its ability to reverse MDR caused by the overexpression of ABCB1. Cytotoxicity of ciprofloxacin was determined by the MTT assay. The chemosensitizing effects of ciprofloxacin were determined in combination with ABCB1 substrates. The intracellular accumulation and efflux of ABCB1 substrates was measured by a scintillation counter, and protein expression was determined by the Western blotting. Vanadate-sensitive ATPase assay was performed to determine the effect of ciprofloxacin on the ATPase activity of ABCB1, and docking analysis was done to determine the interaction of ciprofloxacin with ABCB1. Ciprofloxacin significantly potentiated the cytotoxic effects of ABCB1 substrates in ABCB1-overexpressing cells. Furthermore, ciprofloxacin increased the intracellular accumulation and decreased the efflux of [³H]-paclitaxel without altering the expression of ABCB1. Ciprofloxacin stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. Our findings showed that ciprofloxacin potently inhibits the ABCB1 efflux function and it has potential to be developed as a combination anticancer therapy.
ABCB1 是一种主要的药物外排转运蛋白，已知它会导致接受化疗治疗实体瘤和血液恶性肿瘤的癌症患者产生多药耐药性（MDR）。抑制 ABCB1 的外排功能对于维持化疗药物的细胞内浓度很重要。在这里，我们评估了环丙沙星逆转 ABCB1 过表达引起的 MDR 的能力。通过 MTT 测定法测定环丙沙星的细胞毒性。通过与 ABCB1 底物联合测定环丙沙星的化学增敏作用。通过闪烁计数器测量 ABCB1 底物的细胞内积累和外排，通过 Western 印迹测定蛋白表达。通过钒酸盐敏感的 ATP 酶测定法测定环丙沙星对 ABCB1 的 ATP 酶活性的影响，并进行对接分析以确定环丙沙星与 ABCB1 的相互作用。环丙沙星在 ABCB1 过表达细胞中显著增强了 ABCB1 底物的细胞毒性作用。此外，环丙沙星增加了[³H]-紫杉醇的细胞内积累并减少了其外排，而不改变 ABCB1 的表达。环丙沙星以浓度依赖的方式刺激 ABCB1 的 ATP 酶活性。我们的研究结果表明，环丙沙星强烈抑制 ABCB1 的外排功能，有潜力开发为联合抗癌疗法。
