Teng Qiu-Xu, Luo Xiaofang, Lei Zi-Ning, Wang Jing-Quan, Wurpel John, Qin Zuodong, Yang Dong-Hua
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Research Center of Biochemical Engineering Technology, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425199, China.
Cancers (Basel). 2020 Jul 19;12(7):1963. doi: 10.3390/cancers12071963.
The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.
ATP结合盒（ABC）转运蛋白的过表达是癌症多药耐药（MDR）的常见原因。由于作为抗癌药外排泵的ABC转运蛋白表达增加，癌细胞的细胞内药物浓度相对于其正常细胞会降低。在过去几十年中，抗菌肽已作为新一代抗癌药进行了研究，据报道其中一些抗菌肽与ABC转运蛋白有相互作用。在本文中，我们研究了几种新型抗菌肽，以观察它们是否能使过表达ABCB1的细胞对由ABCB1转运的抗癌药紫杉醇和阿霉素敏感。结果发现，肽XH-14C增加了ABCB1底物紫杉醇的细胞内蓄积，这表明XH-14C可以逆转ABCB1介导的多药耐药。此外，XH-14C可以刺激ABCB1的ATP酶活性，分子动力学模拟揭示了XH-14C-ABCB1复合物的稳定结合构象。用XH-14C处理后，ABCB1转运蛋白的表达水平和位置没有变化。我们的结果表明，XH-14C与传统抗癌药联合使用可作为一种新型癌症治疗策略。
