Targeting cisplatin-resistant human tumor cells with metabolic inhibitors

Elizabeth J. Sullivan, Metin Kurtoglu, Randall Brenneman, Huaping Liu, Theodore Lampidis

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)417-427
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number2
DOIs
StatePublished - Jan 1 2014

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Cisplatin
Tumors
Cells
Neoplasms
Cell Line
Lung Neoplasms
Cell death
Cell Death
Glutamine
Fatty Acids
Oxygen
Oxidation
Mitochondria
Hexokinase
Deoxyglucose
Glycolysis
Cytotoxicity
Tumor Cell Line
Metabolism
Ovarian Neoplasms

Keywords

  • 2-Deoxy-d-glucose
  • Cell death
  • Cisplatin resistance
  • Hexokinase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Targeting cisplatin-resistant human tumor cells with metabolic inhibitors. / Sullivan, Elizabeth J.; Kurtoglu, Metin; Brenneman, Randall; Liu, Huaping; Lampidis, Theodore.

In: Cancer Chemotherapy and Pharmacology, Vol. 73, No. 2, 01.01.2014, p. 417-427.

Research output: Contribution to journalArticle

Sullivan, Elizabeth J. ; Kurtoglu, Metin ; Brenneman, Randall ; Liu, Huaping ; Lampidis, Theodore. / Targeting cisplatin-resistant human tumor cells with metabolic inhibitors. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 73, No. 2. pp. 417-427.
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