title: Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting.
abstract: The anticancer efficacy of the pyruvate analog 3-bromopyruvate has been demonstrated in multiple tumor models. The chief principle underlying the antitumor effects of 3-bromopyruvate is its ability to effectively target the energy metabolism of cancer cells. Biochemically, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as the primary target of 3-bromopyruvate. Its inhibition results in the depletion of intracellular ATP, causing cell death. Several reports have also demonstrated that in addition to GAPDH inhibition, the induction of cellular stress also contributes to 3-bromopyruvate treatment-dependent apoptosis. Furthermore, recent evidence shows that 3-bromopyruvate is taken up selectively by tumor cells via the monocarboxylate transporters (MCTs) that are frequently overexpressed in cancer cells (for the export of lactate produced during aerobic glycolysis). The preferential uptake of 3-bromopyruvate via MCTs facilitates selective targeting of tumor cells while leaving healthy and non-malignant tissue untouched. Taken together, the specificity of molecular (GAPDH) targeting and selective uptake by tumor cells, underscore the potential of 3-bromopyruvate as a potent and promising anticancer agent. In this review, we highlight the mechanistic characteristics of 3-bromopyruvate and discuss its potential for translation into the clinic.
authors.affiliation: Professor of Radiology, Surgery and Oncology, Director, Vascular and Interventional Radiology, Director, Interventional Radiology Center, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Suite 7203, The Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21287, USA.
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Ganapathy-Kanniappan
authors.forename: Rani
authors.initials: R
authors.lastname: Kunjithapatham
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Geschwind
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011773:Pyruvates / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D027501:Monocarboxylic Acid Transporters; D011773:Pyruvates; C017092:bromopyruvate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases