Journal
MOLECULAR ONCOLOGY
Volume 2, Issue 1, Pages 94-101Publisher
WILEY
DOI: 10.1016/j.molonc.2008.01.003
Keywords
Glycolysis; Adenosine triphosphate; Chemotherapy; Cisplatin; Oxaliplatin; p53; Chemopotentiation
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Funding
- Swedish Cancer Society
- Cancerforeningen Research Foundation
- Anna Brita and Bo Castegrens Memorial Foundation
- Ollie and Elof Ericsson Memorial Foundation
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Tumour cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, making energy metabolism an interesting therapeutic target. 3-Bromopyruvate (BP) has been shown by others to inhibit hexokinase and eradicate mouse hepatocarcinomas. We report that similar to the glycolysis inhibitor 2-deoxyglucose (DG), BP rapidly decreased cellular ATP within hours, but unlike DG, BP concomitantly induced mitochondrial. depolarization without affecting levels of reducing equivalents. Over 24 h, and at equitoxic doses, DG reduced glucose consumption more than did BP. The observed BP-induced loss of ATP is therefore largely due to mitochondrial effects. Cell death induced over 24 h by BP, but not DG, was blocked by N-acetylcysteine, indicating involvement of reactive oxygen species. BP-induced cytotoxicity, was independent of p53. When combined with cisplatin or oxaliplatin, BP led to massive cell death. The anti-proliferative effects of low-dose platinum were strikingly potentiated also in resistant p53-deficient cells. Together with the reported lack of toxicity, this indicates the potential of BP as a clinical chemopotentiating agent. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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