title: Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Shengchao
authors.initials: S
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Kecheng
authors.initials: K
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Wenpei
authors.initials: W
authors.lastname: Du
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China. Electronic address: yinpeihao1975@hotmail.com.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China. Electronic address: xin.lang@ecust.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China. Electronic address: liujian@ecust.edu.cn.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005978:Glutathione / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D000089762:Multidrug Resistance-Associated Protein 2; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology*; D000077150:Oxaliplatin; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D010778:Photochemotherapy
chemical_list: C000715087:ABCC2 protein, human; D000873:Anthracenes; D000089762:Multidrug Resistance-Associated Protein 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010569:Perylene; C004965:hypericin; D005978:Glutathione
keywords: Glutathione; Glutathione S-transferase (GST); Hypericin; Nucleotide excision repair (NER); Oxaliplatin; Photodynamic therapy (PDT)