Wang Jing-Quan, Li Jonathan Y, Teng Qiu-Xu, Lei Zi-Ning, Ji Ning, Cui Qingbin, Zeng Leli, Pan Yihang, Yang Dong-Hua, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
School of Public Health, Guangzhou Medical University, Guangzhou 511436, Guangdong, China.
Cancers (Basel). 2020 Feb 18;12(2):466. doi: 10.3390/cancers12020466.
Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.
先前的研究表明，小分子BCL-2抑制剂在化疗中可与ABCG2底物产生协同相互作用。维奈克拉是一种强效且具有选择性的BCL-2抑制剂，于2016年获美国食品药品监督管理局（FDA）批准用于治疗慢性淋巴细胞白血病（CLL）患者。本研究表明，在无毒浓度下，10 µM的维奈克拉可显著逆转野生型ABCG2介导的多药耐药（MDR），而对突变型ABCG2（R482G和R482T）及ABCB1介导的MDR无显著影响，在较低浓度（0.5至1 µM）下则观察到中度或无逆转作用。结果显示，维奈克拉增加了化疗药物在细胞内的蓄积，这是直接阻断野生型ABCG2外排功能并抑制ABCG2的ATP酶活性的结果。我们的研究证明，维奈克拉可增强野生型ABCG2底物药物的疗效。这些发现可能为临床实践中针对野生型ABCG2介导的MDR癌症的联合治疗提供有用的指导。
