Open Access3‐Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs
Author(s) -
Ihrlund Linda Strandberg,
Hernlund Emma,
Khan Omar,
Shoshan Maria C.
Publication year - 2008
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2008.01.003
Subject(s) - glycolysis , hexokinase , cisplatin , adenosine triphosphate , cytotoxicity , programmed cell death , mitochondrion , biochemistry , pharmacology , biology , apoptosis , metabolism , chemistry , cancer research , chemotherapy , in vitro , genetics
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 24h, 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 24h 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.