title: The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH.
abstract: Although the anti-cancer properties of 3BP (3-bromopyruvate) have been described previously, its selectivity for cancer cells still needs to be explained [Ko et al. (2001) Cancer Lett. 173, 83-91]. In the present study, we characterized the kinetic parameters of radiolabelled [14C] 3BP uptake in three breast cancer cell lines that display different levels of resistance to 3BP: ZR-75-1 < MCF-7 < SK-BR-3. At pH 6.0, the affinity of cancer cells for 3BP transport correlates with their sensitivity, a pattern that does not occur at pH 7.4. In the three cell lines, the uptake of 3BP is dependent on the protonmotive force and is decreased by MCTs (monocarboxylate transporters) inhibitors. In the SK-BR-3 cell line, a sodium-dependent transport also occurs. Butyrate promotes the localization of MCT-1 at the plasma membrane and increases the level of MCT-4 expression, leading to a higher sensitivity for 3BP. In the present study, we demonstrate that this phenotype is accompanied by an increase in affinity for 3BP uptake. Our results confirm the role of MCTs, especially MCT-1, in 3BP uptake and the importance of cluster of differentiation (CD) 147 glycosylation in this process. We find that the affinity for 3BP transport is higher when the extracellular milieu is acidic. This is a typical phenotype of tumour microenvironment and explains the lack of secondary effects of 3BP already described in in vivo studies [Ko et al. (2004) Biochem. Biophys. Res. Commun. 324, 269-275].
authors: *Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: João
authors: J
authors: Azevedo-Silva
authors: *Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: Odília
authors: O
authors: Queirós
authors: *Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: Ana
authors: A
authors: Ribeiro
authors: ‡Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: Fátima
authors: F
authors: Baltazar
authors: ║KoDiscovery, LLC, University of Maryland BioPark, Suite 502 E & F, 801 West Baltimore St., Baltimore, MD 21201, U.S.A.
authors: Ko H
authors: KH
authors: Young
authors: ¶Departments of Biological Chemistry and Oncology, Member at Large, Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, School of Medicine, Baltimore, MD 21205-2185, U.S.A.
authors: Peter L
authors: PL
authors: Pedersen
authors: *Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: Ana
authors: A
authors: Preto
authors: *Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal.
authors: Margarida
authors: M
authors: Casal
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D051926:Basigin / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011773:Pyruvates / Q000493:pharmacokinetics / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000970:Antineoplastic Agents; D051926:Basigin; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D011773:Pyruvates; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C497886:BSG protein, human; C406962:SLC16A4 protein, human; C017092:bromopyruvate