title: Killing multiple myeloma cells with the small molecule 3-bromopyruvate: implications for therapy.
abstract: The small molecule 3-bromopyruvate (3-BP), which has emerged recently as the first member of a new class of potent anticancer agents, was tested for its capacity to kill multiple myeloma (MM) cancer cells. Human MM cells (RPMI 8226) begin to lose viability significantly within 8 h of incubation in the presence of 3-BP. The Km (0.3 mmol/l) for intracellular accumulation of 3-BP in MM cells is 24 times lower than that in control cells (7.2 mmol/l). Therefore, the uptake of 3-BP by MM cells is significantly higher than that by peripheral blood mononuclear cells. Further, the IC50 values for human MM cells and control peripheral blood mononuclear cells are 24 and 58 µmol/l, respectively. Therefore, specificity and selectivity of 3-BP toward MM cancer cells are evident on the basis of the above. In MM cells the transcription levels of the gene encoding the monocarboxylate transporter MCT1 is significantly amplified compared with control cells. The level of intracellular ATP in MM cells decreases by over 90% within 1 h after addition of 100 µmol/l 3-BP. The cytotoxicity of 3-BP, exemplified by a marked decrease in viability of MM cells, is potentiated by the inhibitor of glutathione synthesis buthionine sulfoximine. In addition, the lack of mutagenicity and its superior capacity relative to Glivec to kill MM cancer cells are presented in this study.
authors.affiliation: aInstitute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland bInstitute of Cell Biology, NAS of Ukraine, Lviv, Ukraine cKoDiscovery LLC, UM BioPark, Innovation Center dDepartments of Biological Chemistry and Oncology, Member Sidney Kimmel Comprehensive Cancer Center, Member Center for Obesity Research and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA eInstitute of Life Sciences, Catholic University of Louvain, Place de l'Université, Louvain-la-Neuve, Belgium.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Majkowska-Skrobek
authors.forename: Daria
authors.initials: D
authors.lastname: Augustyniak
authors.forename: Paweł
authors.initials: P
authors.lastname: Lis
authors.forename: Anna
authors.initials: A
authors.lastname: Bartkowiak
authors.forename: Mykhailo
authors.initials: M
authors.lastname: Gonchar
authors.forename: Young H
authors.initials: YH
authors.lastname: Ko
authors.forename: Peter L
authors.initials: PL
authors.lastname: Pedersen
authors.forename: Andre
authors.initials: A
authors.lastname: Goffeau
authors.forename: Stanisław
authors.initials: S
authors.lastname: Ułaszewski
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D019344:Lactic Acid / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011773:Pyruvates / Q000378:metabolism / Q000494:pharmacology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D001549:Benzamides; D019328:Buthionine Sulfoximine; D005978:Glutathione; D000068877:Imatinib Mesylate; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D010879:Piperazines; D011743:Pyrimidines; D011773:Pyruvates; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C017092:bromopyruvate