Chemosensitizing multiple drug resistance of human carcinoma by Bicyclol involves attenuated p-glycoprotein, GST-P and Bcl-2.
Bicyclol, a second generation of synthetic hepatoprotectant being used in China for anti-hepatitis therapy, shows chemosensitizing effect on reverting multiple drug resistance (MDR) of cytostatic agents in two established MDR carcinoma cell lines, vincristine resistant human stomatic epidermoid carcinoma VinRKB and adriamycin resistant human breast carcinoma AdrRMCF-7. The reversal rate of drug resistance was calculated from the changes of the IC50 of cell growth inhibition. Bicyclol at the concentration of 25, 50, 100 microM induced 2.8 7.3 and 20.7 fold, respectively, reversal of vincristine resistance in VinRKB cell. Bicyclol also reversed the cross-resistance of VinRKB cell to taxol and AdrRMCF-7 cell resistance to adriamycin at the similar range of potency. Further, Bicyclol recovered the reduced accumulation of adriamycin in AdrRMCF-7 cell partially to the level in drug-sensitive MCF-7 cell, indicate the inhibition of MDR related membrane efflux pump system. Overexpression of membrane p-glycoprotein coded by Mdr-1 genes, the most common efflux pump correlated to MDR, was found in both VinRKB and AdrRMCF-7 cells by Western blot and immunocytochemistry as compared with drug-sensitive cells. The p-glycoprotein was decreased to the levels in drug-sensitive cells when VinRKB and AdrRMCF-7 cells were treated with Bicyclol for 12-72 hours. Both VinRKB and AdrRMCF-7 cells showed increased GSH contents, and AdrRMCF-7 cell showed increased GST activity and the overexpression of Bcl-2 protein, by which molecules are tightly related to the MDR formation besides Mdr-1 p-glycoprotein. Bicyclol reduced the GSH contents, GST activities and Bcl-2 expression. All these data demonstrate that, by modifying the expressions of Mdr-1, GSH/GST and Bcl-2, Bicyclol increases the intracellular drug concentration and sensitizes the resistant cells to the anti-carcinoma agents.
Zhu
Bing
B
University of South Alabama College of Medicine, Department of Pharmacology, Mobile, Alabama 36688, USA. zbing@jaguar1.usoutha1.edu
Liu
Geng Tao
GT
Zhao
Yong Mei
YM
Wu
Ruo Su
RS
Strada
Samuel J
SJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014750:Vincristine; C477843:bicyclol; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005978:Glutathione