Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism
Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism
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金丝桃素介导的ROS相关机制光动力疗法增强人结直肠癌奥沙利铂敏感性
DOI：
10.1016/j.biocel.2015.12.003
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Liu, Jianwen
中科院分区：
文献类型：
--
作者：
Lin, Shengchao;Lei, Kecheng;Liu, Jianwen
奥沙利铂（L-OHP）耐药是结直肠癌获得理想治疗结果的主要障碍。光动力疗法（PDT）通过光敏剂介导的氧化细胞毒性诱导肿瘤损伤。金丝桃素是一种被充分研究的光敏剂。在这项研究中，我们探讨了金丝桃素介导的光动力学（HY-PDT）在人大肠癌细胞对L-OHP的增敏作用。HY-PDT预处理可通过减少药物外排和增加铂蓄积而增强L-OHP的抗肿瘤活性。进一步的研究表明，HY-PDT介导的耐药细胞对L-OHP的再敏感依赖于MRP-2的调节，而不是P-gp。HY-PDT还被发现抑制细胞内谷胱甘肽（GSH）和谷胱甘肽S-转移酶（GST），这表明GSH相关的解毒参与敏化作用。此外，HY-PDT/L-OHP联合治疗后观察到DNA双链断裂（DSB）增强。HY-PDT可降低铂的去除率，下调核苷酸切除修复（NER）途径中两个关键酶ERCC 1和XPF的表达。GSH单乙酯（GSH-EE）拮抗HY-PDT诱导的ROS和抑制敏感铂。综上所述，HY-PDT介导的L-OHP在人结直肠癌中的增敏是由ROS介导的，其机制涉及影响药物外排、GSH相关的解毒和NER介导的DNA修复。(C)2015爱思唯尔有限公司版权所有。
The resistance to oxaliplatin (L-OHP) is a major obstacle to ideal therapeutic outcomes in colorectal cancer. Photodynamic therapy (PDT) induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a well-studied photosensitizer. In this study, we explored the role of hypericin-mediated PDT (HY-PDT) in sensitizing human colorectal cancer cells towards L-OHP. Pre-treatment with HY-PDT enhanced the anti-tumor activity of L-OHP via decreasing drug efflux and increasing platinum accumulation. Further research showed that HY-PDT-mediated resensitization of resistance cells towards L-OHP was dependent on regulation of MRP-2, instead of p-gp. HY-PDT was also found to inhibit intracellular glutathione (GSH) and Glutathione S-transferase (GST), suggesting the involvement of GSH-related detoxification in the sensitization effect. Additionally, enhanced DNA double-strand breaks (DSBs) was observed following HY-PDT/L-OHP combined treatment. HY-PDT lowered the removing rate of platinum from DNA and down-regulated the expression of ERCC1 and XPF, two critical enzymes involved in nucleotide excision repair (NER) pathway. GSH monoethyl ester (GSH-EE) antagonized HY-PDT-induced ROS and repressed sensitization to platinum. Taken together, HY-PDT mediated sensitization of L-OHP in human colorectal cancer is mediated by ROS, whose mechanism involves affecting drug efflux, GSH-related detoxification and NER-mediated DNA repair. (C) 2015 Elsevier Ltd. All rights reserved.