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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Targeting cisplatin-resistant human tumor cells with metabolic inhibitors
Elizabeth J Sullivan1, Metin Kurtoglu, Randall Brenneman
1Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, P.O. Box 016960 (R124), Miami, FL, 33101, USA.
Purpose:
Although cisplatin is the drug of choice in treating lung cancer patients, relapse and resistance is a common drawback to its clinical effectiveness. Based on cisplatin's reported ability to interfere with numerous cellular components, including mitochondria, we probed alterations in metabolism in cisplatin-resistant tumor cell lines to reveal targets for overcoming this important form of resistance.
Methods:
Cisplatin-resistant lung and ovarian cancer cell lines were used to evaluate the efficacy of metabolic inhibitors for selectively targeting cisplatin-resistant cells under varying oxygen conditions.
Results:
Three cisplatin-resistant cancer cell lines expressed lower HKII protein when compared to the respective cisplatin-sensitive cancer cell lines from which they were derived. Under anaerobic and hypoxic conditions, treatment with the glycolytic inhibitors 2-deoxyglucose (2-DG) and 2-fluorodeoxyglucose (2-FDG) correlated with increased cytotoxicity and more pronounced decreases in lactate production in cisplatin-resistant cells, indicating a greater blockage of glycolysis. Knockdown of HKI or HKII with siRNA in the parental lung cancer cell lines led to increased 2-FDG-induced cell death under anaerobic conditions. Under normal oxygen conditions, blockage of either fatty acid oxidation or deprivation of glutamine resulted in cell death in cisplatin-resistant lung cancer cell lines.
Conclusions:
Altered hexokinase levels in cisplatin-resistant cancer cell lines leads to increased sensitivity to glycolytic inhibition under anaerobic conditions, whereas under normoxic conditions, blockage of either fatty acid oxidation or deprivation of glutamine leads to cell death. These findings may be clinically applicable when considering cisplatin resistance.
Insights
Cisplatin resistance in cancer cells can be overcome by targeting their altered metabolism. Inhibiting glycolysis under low oxygen or blocking fatty acid oxidation/glutamine under normal oxygen shows promise for treating resistant lung and ovarian cancers.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Resistance
Background:
- Cisplatin is a primary lung cancer treatment, but resistance and relapse limit its effectiveness.
- Cisplatin's interaction with cellular components, including mitochondria, suggests metabolic pathways are key to resistance.
- Understanding metabolic alterations in resistant cells can reveal strategies to overcome cisplatin resistance.
Purpose of the Study:
- To investigate metabolic alterations in cisplatin-resistant cancer cell lines.
- To identify metabolic targets for overcoming cisplatin resistance in lung and ovarian cancers.
- To evaluate the efficacy of metabolic inhibitors against cisplatin-resistant cells under various oxygen conditions.
Main Methods:
- Utilized cisplatin-resistant and sensitive lung and ovarian cancer cell lines.
- Assessed the impact of metabolic inhibitors (glycolytic, fatty acid oxidation) and nutrient deprivation (glutamine).
- Examined cellular responses under varying oxygen conditions (anaerobic, hypoxic, normoxic).
- Measured cytotoxicity, lactate production, and protein expression (HKII).
- Employed siRNA to knock down hexokinase (HKI/HKII) expression.
Main Results:
- Cisplatin-resistant cell lines showed reduced hexokinase II (HKII) protein levels.
- Glycolytic inhibitors (2-DG, 2-FDG) increased cytotoxicity and reduced lactate in resistant cells under anaerobic/hypoxic conditions.
- Knockdown of HKI or HKII enhanced 2-FDG-induced cell death in resistant lung cancer cells anaerobically.
- Blocking fatty acid oxidation or glutamine deprivation induced cell death in resistant lung cancer cells under normoxic conditions.
Conclusions:
- Altered hexokinase levels in cisplatin-resistant cells enhance sensitivity to glycolytic inhibition under anaerobic conditions.
- Targeting fatty acid oxidation or glutamine is effective against cisplatin-resistant cells under normoxic conditions.
- These metabolic vulnerabilities offer potential clinical strategies for managing cisplatin resistance in lung and ovarian cancers.
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