Abstract
3-Bromopyruvic acid (3-BP) is a promising anticancer compound because it is a strong inhibitor of glycolytic enzymes, especially glyceraldehyde 3-phosphate dehydrogenase. The Warburg effect means that malignant cells are much more dependent on glycolysis than normal cells. Potential complications of anticancer therapy with 3-BP are side effects due to its interaction with normal cells, especially erythrocytes. Transport into cells is critical for 3-BP to have intracellular effects. The aim of our study was the kinetic characterization of 3-BP transport into human erythrocytes. 3-BP uptake by erythrocytes was linear within the first 3 min and pH-dependent. The transport rate decreased with increasing pH in the range of 6.0–8.0. The Km and Vm values for 3-BP transport were 0.89 mM and 0.94 mmol/(l cells x min), respectively. The transport was inhibited competitively by pyruvate and significantly inhibited by DIDS, SITS, and 1-cyano-4-hydroxycinnamic acid. Flavonoids also inhibited 3-BP transport: the most potent inhibition was found for luteolin and quercetin.
Article PDF
Abbreviations
- 3-BP:
-
3-bromopyruvate
- CHC:
-
1-cyano-4-hydroxycinnamic acid
- DIDS:
-
4,4′-diisothiocyanostilbene-2,2′-disulphonate
- MCT:
-
monocarboxylate transporter
- SITS:
-
4-acetamido-4′-isothiocyanostilbene-2,2′-disulphonic acid
References
Schaefer, N.G., Geschwind, J.F., Engle, J., Buchanan, J.W. and Wahl, R.L. Systemic administration of 3-bromopyruvate in treating disseminated aggressive lymphoma. Transl. Res. 159 (2012) 51–57.
Ko, Y.H., Pedersen, P.L. and Geschwind, J.F. Glucose metabolism in the rabbit VX tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett. 173 (2001) 83–91.
Sánchez-Aragó, M. and Cuezva, J.M. The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil. J. Transl. Med. 9 (2011) 19.
Tang, Z., Yuan, S., Hu, Y., Zhang, H., Wu, W., Zeng, Z., Yang, J., Yun, J., Xu, R. and Huang, P. Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester. J. Bioenerg. Biomembr. 44 (2012) 117–125.
Queirós, O., Preto, A., Pacheco, A., Pinheiro, C., Azevedo-Silva, J., Moreira, R., Pedro, M., Ko, Y.H., Pedersen, P.L., Baltazar, F. and Casal, M. Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. J. Bioenerg. Biomembr. 44 (2012) 141–153.
Ko, Y.H., Smith, B.L., Wang, Y., Pomper, M.G., Rini, D.A, Torbenson, M.S., Hullihen, J. and Pedersen, P.L. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem. Biophys. Res. Commun. 324 (2004) 269–275.
Ganapathy-Kanniappan, S., Kunjithapatham, R. and Geschwind, J.F. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting. Anticancer Res. 33 (2013) 13–20.
Lea, M.A., Qureshi, M.S., Buxhoeveden, M., Gengel, N., Kleinschmit, J. and Desbordes, C. Regulation of the proliferation of colon cancer cells by compounds that affect glycolysis, including 3-bromopyruvate, 2-deoxyglucose and biguanides. Anticancer Res. 33 (2013) 401–407.
Lis, P., Zarzycki, M., Ko, Y.H., Casal, M., Pedersen, P.L., Goffeau, A. and Ulaszewski, S. Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae. J. Bioenerg. Biomembr. 44 (2012) 155–161.
Dean, M., Hamon, Y. and Chimini, G. The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42 (2001) 1007–1017.
Geschwind, J.F., Ko, Y.H., Torbenson, M.S., Magee, C. and Pedersen, P.L. Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res. 62 (2002) 3909–3913.
Chang, J.M., Chung, J.W., Jae, H.J., Eh, H., Son, K.R., Lee, K.C. and Park, J.H. Local toxicity of hepatic arterial infusion of hexokinase II inhibitor, 3-bromopyruvate: In vivo investigation in normal rabbit model. Acad. Radiol. 14 (2007) 85–92.
Dell’Antone, P. Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent. Med. Chem. 5 (2009) 491–496.
Sadowska-Bartosz, I. and Bartosz, G. The effect of 3-bromopyruvic acid on human erythrocyte antioxidant defense system. Cell Biol. Int. 2013, in press; DOI: 10.1002/cbin.10160.
Dyląg, M., Lis, P., Niedźwiecka, K., Ko, Y.H., Pedersen, P.L., Goffeau, A. and UŁaszewski, S. 3-bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans. Biochem. Biophys. Res. Commun. 434 (2013) 322–327.
Janas, T. and Janas, T. Involvement of carboxyl groups in chloride transport and reversible DIDS binding to band 3 protein in human erythrocytes. Cell. Mol. Biol. Lett. 16 (2011) 342–358.
Kennedy, K.M. and Dewhirst, M.W. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 6 (2010) 127–148.
Birsoy, K., Wang, T., Possemato, R., Yilmaz, O.H., Koch, C.E., Chen, W.W., Hutchins, A.W., Gultekin, Y., Peterson, T.R., Carette, J.E., Brummelkamp, T.R., Clish, C.B. and Sabatini, D.M. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat. Genet. 45 (2013) 104–108.
Halestrap, A.P. and Meredith, D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447 (2004) 619–628.
Dhup, S., Dadhich, R.K., Porporato, P.E. and Sonveaux, P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr. Pharm. Des. 18 (2012) 1319–1330.
Ullah, M.S., Davies, A.J. and Halestrap, A.P. The plasma membrane lactate transporter MsCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem. 281 (2006) 9030–9037.
Draoui, N, and Feron, O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis. Model. Mech. 4 (2011) 727–732.
Halestrap, A.P. The monocarboxylate transporter family — structure and functional characterization. IUBMB Life 64 (2012) 1–9.
Kunjithapatham, R., Geschwind, J.F., Rao, P.P., Boronina, T.N., Cole, R.N. and Ganapathy-Kanniappan, S. Systemic administration of 3-bromopyruvate reveals its interaction with serum proteins in a rat model. BMC Res. Notes 17 (2013) 277.
Belt, J.A., Thomas, J.A., Buchsbaum, R.N. and Racker, E. Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids. Biochemistry 18 (1979) 3506–3511.
Vaidyanathan, J.B. and Walle, T. Cellular uptake and efflux of the tea flavonoid (-) epicatechin-3-gallate in the human intestinal cell line Caco-2. J. Pharmacol. Exp. Ther. 307 (2003) 745–752.
Di Pietro, A., Conseil, G., Pérez-Victoria, J.M., Dayan, G., Baubichon-Cortay, H., Trompier, D., Steinfels, E., Jault, J.M., de Wet, H., Maitrejean, M., Comte, G., Boumendjel, A., Mariotte, A.M., Dumontet, C., McIntosh, D.B., Goffeau, A., Castanys, S., Gamarro, F. and Barron, D. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol. Life Sci. 59 (2002) 307–322.
Zhang, S. and Morris, M.E. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J. Pharmacol. Exp. Ther. 304 (2003) 1258–1267.
Ahmed-Belkacem, A., Pozza, A., Munoz-Martínez, F., Bates, S.E., Castanys, S., Gamarro, F., Di Pietro, A. and Pérez-Victoria, J.M. Flavonoid structure-activity studies identify 6-prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res. 65 (2005) 4852–4860.
Morris, M.E. and Zhang, S. Flavonoid-drug interactions: effects of flavonoids on ABC transporters. Life Sci. 78 (2006) 2116–2130.
Wang, X., Wolkoff, A.W. and Morris, M.E. Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab. Dispos. 33 (2005) 1666–1672.
Fuchikami, H., Satoh, H., Tsujimoto, M., Ohdo, S., Ohtani, H. and Sawada, Y. Effects of herbal extracts on the function of human organic aniontransporting polypeptide OATP-B. Drug Metab. Dispos. 34 (2006) 577–582.
Wang, Q. and Morris, M.E. Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab. Dispos. 35 (2007) 201–208.
Poole, R.C. and Halestrap, A.P. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am. J. Physiol. Cell Physiol. 264 (1993) C761–C782.
Vaihkonen, L.K., Heinonen, O.J., Hyyppa, S., Nieminen, M. and Poso, A.R. Lactate-transport activity in RBCs of trained and untrained individuals from four racing species. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281 (2001) R19–R24.
Barreca, D., Lagana, G., Tellone, E., Ficarra, S., Leuzzi, U., Galtieri, A. and Bellocco, E. Influences of flavonoids on erythrocyte membrane and metabolic implication through anionic exchange modulation. J. Membr. Biol. 230 (2009) 163–171.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sadowska-Bartosz, I., Soszyński, M., Ułaszewski, S. et al. Transport of 3-bromopyruvate across the human erythrocyte membrane. Cell Mol Biol Lett 19, 201–214 (2014). https://doi.org/10.2478/s11658-014-0189-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.2478/s11658-014-0189-1