Zinc protoporphyrin IX enhances chemotherapeutic response of hepatoma cells to cisplatin

• Published in: World journal of gastroenterology : WJG 2014-07, Vol.20 (26), p.8572-8582
• Main Authors: Liu, Yang-Sui, Li, Huan-Song, Qi, Dun-Feng, Zhang, Jun, Jiang, Xin-Chun, Shi, Kui, Zhang, Xiao-Jun, Zhang, Xin-Hui
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; canc; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Caspase 3 - metabolism; Cisplatin - administration & dosage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Heme; Heme Oxygenase-1 - metabolism; Hemin - pharmacology; Hep G2 Cells; Humans; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice, Nude; Original; Oxidative Stress - drug effects; oxygenase-1; protoporphyrin; Protoporphyrins - administration & dosage; Reactive Oxygen Species - metabolism; Time Factors; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Zinc
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v20.i26.8572

AIM:To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved.METHODS:Cytotoxicity was determined using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Apoptosis was determined by a flow cytometric assay.Western blotting was used to measure protein expression.Heme oxygenase(HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes.Reactive oxygen species(ROS)production was monitored by flow cytometry.Caspase-3 activity was measured with a colorimetric assay kit.Mice were inoculated with 1×107 tumor cells subcutaneously into the right flanks.All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured.RESULTS:Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cisdiaminedichloroplatinum(cisplatin;CDDP)compared to other cell lines in vitro.Inhibition of HO-1 expression or activity by zinc protoporphyrin IX(ZnPP IX)markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo.In contrast,induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo.Furthermore,cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity,which paralleled the incidence of cell apoptosis,whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP.CONCLUSION:ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS.