Li Yan-Chi, Xiong Yu-Meng, Long Ze-Ping, Huang Yi-Ping, Shu Yu-Bin, He Ke, Sun Hong-Yan, Shi Zhi
Cancer Minimally Invasive Therapies Centre, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510632, China.
Department of Cell Biology & Institute of Biomedicine, Guangdong Provincial Biotechnology & Engineering Technology Research Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Genomic Medicine Engineering Research Center of Ministry of Education, MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
Biomedicines. 2025 May 20;13(5):1245. doi: 10.3390/biomedicines13051245.
ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Cytotoxicity assays (MTT) were performed on ABCB1-overexpressing HCT-8/V and ABCG2-overexpressing S1-M1-80 CRC cells. Drug accumulation (doxorubicin/mitoxantrone) was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. Molecular docking utilized the ABCB1 crystal structure. ML210 selectively reversed ABCB1-mediated resistance to doxorubicin and vincristine in HCT-8/V cells, enhancing intracellular drug accumulation without affecting ABCG2 activity. It induced cell cycle arrest in ABCB1-overexpressing cells and did not alter ABCB1 protein expression. Molecular docking revealed stable binding of ML210 within the ABCB1 substrate pocket through hydrophobic interactions and hydrogen bonding. ML210 is a selective ABCB1 inhibitor that circumvents MDR via direct transport blockade, offering a targeted strategy against ABCB1-mediated chemoresistance in CRC. Its specificity for ABCB1 over ABCG2 highlights potential clinical advantages.
ABCB1介导的多药耐药性（MDR）会降低结直肠癌（CRC）的化疗疗效。尽管经过数十年的研究，但尚无选择性ABCB1抑制剂取得临床成功。本研究调查了ML210作为一种新型ABCB1特异性抑制剂，以逆转ABCB1驱动的MDR。对过表达ABCB1的HCT-8/V细胞和过表达ABCG2的S1-M1-80 CRC细胞进行了细胞毒性试验（MTT）。通过流式细胞术对药物蓄积（多柔比星/米托蒽醌）进行定量，并使用碘化丙啶染色分析细胞周期效应。分子对接利用了ABCB1晶体结构。ML210选择性地逆转了HCT-8/V细胞中ABCB1介导的对多柔比星和长春新碱的耐药性，增加了细胞内药物蓄积，而不影响ABCG2活性。它在过表达ABCB1的细胞中诱导细胞周期停滞，且不改变ABCB1蛋白表达。分子对接显示，ML210通过疏水相互作用和氢键在ABCB1底物口袋内稳定结合。ML210是一种选择性ABCB1抑制剂，通过直接阻断转运来规避MDR，为针对CRC中ABCB1介导的化疗耐药性提供了一种靶向策略。其对ABCB1而非ABCG2的特异性突出了潜在的临床优势。
