DataSheet2_Dorsomorphin attenuates ABCG2-mediated multidrug resistance in colorectal cancer.ZIP

Colorectal cancer is a common malignant tumor with high mortality, for which chemotherapy resistance is one of the main reasons. The high expression of ABCG2 in the cancer cells and expulsion of anticancer drugs directly cause multidrug resistance (MDR). Therefore, the development of new ABCG2 inhibitors that block the active causes of MDR may provide a strategy for the treatment of colorectal cancer. In this study, we find that dorsomorphin (also known as compound C or BML-275) potently inhibits the transporter activity of ABCG2, thereby preserving the chemotherapeutic agents mitoxantrone and doxorubicin to antagonize MDR in ABCG2-overexpressing colorectal cancer cells. Additionally, dorsomorphin does not alter ABCG2 protein expression. The results of molecular docking studies show that dorsomorphin is bound stably to the ABCG2-binding pocket, suggesting that dorsomorphin is a potent ABCG2 inhibitor that attenuates ABCG2-mediated MDR in colorectal cancer.

结直肠癌是一种高发且高致死率的恶性肿瘤，化疗耐药是导致其高死亡率的主要原因之一。ABCG2在癌细胞中的高表达及对抗肿瘤药物的外排作用，会直接引发多药耐药（multidrug resistance, MDR）。因此，研发能够阻断多药耐药核心致病机制的新型ABCG2抑制剂，可为结直肠癌的治疗提供新策略。本研究发现，多索莫芬（dorsomorphin，又名compound C或BML-275）可强效抑制ABCG2的转运活性，从而使化疗药物米托蒽醌（mitoxantrone）与多柔比星（doxorubicin）能够有效拮抗ABCG2过表达结直肠癌细胞中的多药耐药。此外，多索莫芬不会改变ABCG2的蛋白表达水平。分子对接实验结果显示，多索莫芬可稳定结合于ABCG2的结合口袋，这表明多索莫芬是一种强效ABCG2抑制剂，能够减弱结直肠癌细胞中ABCG2介导的多药耐药。