Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular and Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan.
Molecular and Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
Biomed Pharmacother. 2022 Oct;154:113663. doi: 10.1016/j.biopha.2022.113663. Epub 2022 Sep 5.
The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer cells. These transporters are capable of reducing the efficacy of cytotoxic drugs by actively effluxing them out of cancer cells. Since there is currently no approved treatment for patients with multidrug-resistant tumors, the drug repurposing approach provides an alternative route to identify agents to reverse MDR mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. WDR5-0103 is a histone H3 lysine 4 (H3K4) methyltransferase inhibitor that disrupts the interaction between the WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia (MLL) protein. In this study, the effect of WDR5-0103 on MDR mediated by ABCB1 and ABCG2 was determined. We found that in a concentration-dependent manner, WDR5-0103 could sensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to conventional cytotoxic drugs. Our results showed that WDR5-0103 reverses MDR and improves drug-induced apoptosis in multidrug-resistant cancer cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, without altering the protein expression of ABCB1 or ABCG2. The potential sites of interactions of WDR5-0103 with the drug-binding pockets of ABCB1 and ABCG2 were predicted by molecular docking. In conclusion, the MDR reversal activity of WDR5-0103 demonstrated here indicates that it could be used in combination therapy to provide benefits to a subset of patients with tumor expressing high levels of ABCB1 or ABCG2.
多药耐药（MDR）的发展是癌症治疗中的主要挑战之一，这是由于癌细胞中 ATP 结合盒（ABC）转运蛋白 ABCB1（P-糖蛋白）和/或 ABCG2（BCRP/MXR/ABCP）的过度表达引起的。这些转运蛋白能够通过将细胞毒性药物主动排出癌细胞来降低其疗效。由于目前尚无针对多药耐药肿瘤患者的批准治疗方法，因此药物再利用方法为识别能够逆转 ABCB1 和/或 ABCG2 介导的多药耐药癌细胞中的 MDR 的药物提供了另一种途径。WDR5-0103 是一种组蛋白 H3 赖氨酸 4（H3K4）甲基转移酶抑制剂，可破坏 WD 重复蛋白 5（WDR5）和混合谱系白血病（MLL）蛋白之间的相互作用。在这项研究中，确定了 WDR5-0103 对 ABCB1 和 ABCG2 介导的 MDR 的影响。我们发现，WDR5-0103 以浓度依赖性方式能够使 ABCB1 和 ABCG2 过表达的多药耐药癌细胞对常规细胞毒性药物敏感。我们的结果表明，WDR5-0103 通过抑制 ABCB1 和 ABCG2 的药物外排功能逆转 MDR 并改善多药耐药癌细胞中的药物诱导凋亡，而不改变 ABCB1 或 ABCG2 的蛋白表达。通过分子对接预测了 WDR5-0103 与 ABCB1 和 ABCG2 的药物结合口袋相互作用的潜在位点。总之，这里显示的 WDR5-0103 的 MDR 逆转活性表明，它可用于联合治疗，为表达高水平 ABCB1 或 ABCG2 的肿瘤患者提供益处。
