Document Detail


Multidrug-resistant hela cells overexpressing MRP1 exhibit sensitivity to cell killing by hyperthermia: interactions with etoposide.
MedLine Citation:
PMID:  15590186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Multidrug resistance (MDR) remains one of the primary obstacles in cancer chemotherapy and often involves overexpression of drug efflux transporters such as P-glycoprotein and multidrug resistance protein 1 (MRP1). Regional hyperthermia is undergoing clinical investigation in combination with chemotherapy or radiotherapy. This study evaluates whether hyperthermia can reverse MDR mediated by MRP1 in human cervical adenocarcinoma (HeLa) cells. METHODS AND MATERIALS: Cytotoxicity of hyperthermia and/or etoposide was evaluated using sulforhodamine-B in HeLa cells overexpressing MRP1 and their drug-sensitive counterparts. Glutathione, glutathione peroxidase (GPx), and glutathione S-transferase (GST) were quantified by spectrophotometry. GST isoenzymes were quantified by immunodetection. Caspase activation was evaluated by fluorometry and chromatin condensation by fluorescence microscopy using Hoechst 33258. Necrosis was determined using propidium iodide. RESULTS: The major finding is that HeLa and HeLaMRP cells are both sensitive to cytotoxicity of hyperthermia (41-45 degrees C). Hyperthermia induced activation of caspase 3 and chromatin condensation. Although total levels of cell killing were similar, there was a switch from apoptotic to necrotic cell death in MDR cells. This could be explained by decreased glutathione and GPx in MDR cells. MDR cells also contained very low levels of GST and were resistant to etoposide-induced apoptosis. Hyperthermia caused a modest increase in etoposide-induced apoptosis in HeLa and HeLaMRP cells, which required appropriate heat-drug scheduling. CONCLUSIONS: Hyperthermia could be useful in eliminating MDR cells that overexpress MRP1.
Authors:
Tatiana Souslova; Diana A Averill-Bates
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  60     ISSN:  0360-3016     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-13     Completed Date:  2005-01-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1538-51     Citation Subset:  IM    
Affiliation:
Département de Chimie et de Biochimie, Université du Québec à Montréal, Succursale Centre Ville, Montréal, Québec, Canada.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / therapeutic use*
Apoptosis / physiology
Caspase 3
Caspases / metabolism
Combined Modality Therapy
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Etoposide / therapeutic use*
Glutathione / metabolism
Glutathione Peroxidase / metabolism
Glutathione Transferase / metabolism
Hela Cells / drug effects,  metabolism*
Humans
Hyperthermia, Induced*
Multidrug Resistance-Associated Proteins / metabolism*
P-Glycoprotein / metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Multidrug Resistance-Associated Proteins; 0/P-Glycoprotein; 33419-42-0/Etoposide; 70-18-8/Glutathione; EC 1.11.1.9/Glutathione Peroxidase; EC 2.5.1.18/Glutathione Transferase; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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