3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs.
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.
Ihrlund
Linda Strandberg
LS
Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institute, S-171 76 Stockholm, Sweden.
Hernlund
Emma
E
Khan
Omar
O
Shoshan
Maria C
MC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003847:Deoxyglucose / Q000494:pharmacology; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017671:Platinum Compounds / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D011773:Pyruvates; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; C017092:bromopyruvate; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D005947:Glucose; D002945:Cisplatin