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Reversal of P-glycoprotein-mediated multidrug resistance in SGC7901/VCR cells by PPARgamma activation by troglitazone.
MedLine Citation:
PMID:  20556576     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Over-expression of P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, represents one of the major mechanisms that contribute to multidrug resistance (MDR) in cancer cells. This study examined the effects of troglitazone, a ligand of peroxisome proliferator-activated receptor gamma (PPARgamma), on P-gp-mediated MDR in SGC7901/VCR cells (a vincristine-resistant human gastric cancer cell line). The expression of P-gp was detected by RT-PCR and Western blotting, respectively. The SGC7901/VCR cells were treated with 0.1 mg/L vincristine (VCR) alone or in combination with 1, 5, 10 micromol/L troglitazone for 24 h. PPARgamma was measured by electrophoretic mobility shift assay (EMSA). The intracellular concentration of Rhodamine123 (Rh123, a fluorescent P-gp substrate) was assayed to evaluate the activity of P-gp. The cell cycle and apoptosis were measured by flow cytometry. The results showed that the P-gp was increasingly expressed in SGC7901, BGC823 and SGC7901/VCR cells in turn, suggesting that MDR in the SGC7901/VCR cells was mediated by the increased expression of P-gp. In the SGC7901/VCR cells, the expression level of total PPARgamma was increased, however, the protein level and activity of PPARgamma in the nuclei of cells decreased significantly. Troglitazone elevated the PPARgamma activity in SGC7901/VCR cells in a dose-dependent manner. Troglitazone decreased the P-gp expression and markedly enhanced the accumulation of Rh123 in SGC7901/VCR cells in a dose-dependent manner. We also found that troglitazone significantly increased the percentage of SGC7901/VCR cells in the G2/M phase and decreased the cell percentage in G1 and S phase in a dose-dependent manner. Troglitazone significantly increased the apoptotic rate of SGC7901/VCR cells treated by VCR or ADR in a dose-dependent manner. It was concluded that P-gp-overexpressed SGC7901/VCR cells have minor endogenous PPARgamma activity. Elevation of the PPARgamma activity by troglitazone can reverse P-gp-mediated MDR via down-regulating the expression and activity of P-gp in SGC7901/VCR cells. It was suggested that troglitazone can dramatically enhance the sensitivity of P-gp-mediated MDR cancer cells to chemotherapeutic agents.
Authors:
Qing Chen; Jie Zhou; Chunfang Jiang; Juan Chen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-17
Journal Detail:
Title:  Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban     Volume:  30     ISSN:  1672-0733     ISO Abbreviation:  J. Huazhong Univ. Sci. Technol. Med. Sci.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101169627     Medline TA:  J Huazhong Univ Sci Technolog Med Sci     Country:  China    
Other Details:
Languages:  eng     Pagination:  326-31     Citation Subset:  IM    
Affiliation:
Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. chenqinga@126.com
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