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Multidrug-resistant hela cells overexpressing MRP1 exhibit sensitivity to cell killing by hyperthermia: interactions
Tatiana Souslova1, Diana A Averill-Bates
1Département de Chimie et de Biochimie, Université du Québec à Montréal, Succursale Centre Ville, Montréal, Québec, Canada.
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.
Insights
Hyperthermia effectively combats multidrug resistance (MDR) in cancer cells by inducing cell death and increasing sensitivity to chemotherapy drugs like etoposide, even in cells overexpressing MRP1.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- Overexpression of drug efflux transporters like P-glycoprotein and multidrug resistance protein 1 (MRP1) contributes to MDR.
- Regional hyperthermia is being investigated as a complementary cancer treatment.
Purpose of the Study:
- To investigate if hyperthermia can overcome MRP1-mediated MDR in human cervical adenocarcinoma (HeLa) cells.
- To evaluate the effects of hyperthermia on cell death pathways in MDR cancer cells.
Main Methods:
- Sulforhodamine-B assay to assess cytotoxicity of hyperthermia and etoposide.
- Quantification of glutathione, glutathione peroxidase (GPx), and glutathione S-transferase (GST).
- Analysis of caspase activation, chromatin condensation, and necrosis.
Main Results:
- HeLa and MRP1-overexpressing HeLa cells showed sensitivity to hyperthermia (41-45°C).
- Hyperthermia induced apoptosis and necrosis, with a shift towards necrosis in MDR cells.
- MDR cells exhibited reduced glutathione and GPx, low GST levels, and resistance to etoposide-induced apoptosis.
- Hyperthermia enhanced etoposide-induced apoptosis in both cell types with specific heat-drug scheduling.
Conclusions:
- Hyperthermia demonstrates potential in eliminating cancer cells overexpressing MRP1.
- Hyperthermia may re-sensitize MDR cancer cells to chemotherapy.
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