Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 71, Issue -, Pages 24-34Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2015.12.003
Keywords
Photodynamic therapy (PDT); Hypericin; Oxaliplatin; Nucleotide excision repair (NER); Glutathione; Glutathione S-transferase (GST)
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Funding
- National Natural Science Foundation of China [81502540]
- Fundamental Research Fund for the Central Universities of China [222201514333]
- Shanghai Committee of Science and Technology [13140902300, 13401900502, 11DZ2260600]
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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.
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