Abstract
Two human leukemia cells K562 and THP-1, the breast cancer lines MCF-7 and ZR-75-1, and the melanoma line MDA-MB-435S were compared by flowcytometry for their behaviour at increasing levels of 3BP. K562 and THP-1 responded to 3BP by membrane depolarization and increased ROS; MCF-7 and ZR-75-1 showed decreased polarization and low ROS increase; MDA-MB-435S had limited depolarization and no ROS increase. THP-1 cells exposed to a range of 3BP concentrations in combination with DCA showed increase of polarization, slight ROS increase, and weakened nuclear integrity. 3BP and DCA show no synergism, but have complementary destructive effects on THP-1 cells. The data led to the conclusion that the THP-1 cells do not carry a functional membrane monocarboxylate transporter (MCT) or that 3BP circumvents MCT binding and can enter these cells independently.
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Arora KK, Pedersen L (1988) Functional significance of mitochondrial bound hexokinase in tumorcell metabolism. J Biol Chem 263:17422–17428
Chang JM, Lee HJ, Jin Mo Goo JM, Lee HY, Lee JJ, Chung JK, Im JG (2006) False positive and false negative FDG-PET scans in various thoracic diseases. Korean J Radiol 7(1):57–69
Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondriaassociated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 1787:553–560
Dell’Antone P (2009) Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent. Med Chem 5:491–496
Ellison G, Klinowska T, Westwood RF, Docter E, French T, Fox JC (2002) Further evidence to support the melanocytic origin of MDA-MB-435. Mol Pathol 55(5):294–299
Engel LW, Young NA, Tralka TS, Lippman ME, O’Brien SJ, Joyce MJ (1978) Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Res 38:3352–3364
Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 62(14):3909–3913
Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343:281–299
Hietakangas V, Poukkula M, Heiskanen KM, Karvinen JT, Sistonen L, Eriksson JE (2003) Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP. Mol Cell Biol 23(4):1278–1291
Jackson VN, Halestrap AP (1996) The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator 2′, 7′bis(carboxymethyl)-5(6)-carboxyfluorescein. J Biol Chem 271:861–868
Kamel R, Schwarzfischer F (1975) Hexokinase isozymes in human neoplastic and fetal tissues: the existence of hexokinase II in malignant tumors and in placenta. Humangenetik 30:181–185
Kim JS, Ahn KJ, Kim JA, Kim HM, Lee JD, Lee JM, Kim SJ, Park JH (2008) Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells: ROS-mediated cell death by 3-BrPA. J Bioenerg Biomembr 40(6):607–618
Ko YH, Pedersen PL, Geschwind JF (2001) Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett 173(1):83–91
Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324(1):269–750
Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45(3):321–334
Mannervik B, Castro VM, Danielson UH, Tahir MK, Hansson J, Ringborg U (1987) Expression of class Pi glutathione transferase in human malignant melanoma cells. Carcinogenesis 8(12):1929–1932
Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2(31):31ra–34ra
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969
Papandreou I, Goliasova T, Denko NC (2011) Anticancer drugs that target metabolism: is dichloroacetate the new paradigm? Int J Cancer 128:1001–1008
Pedersen PL (2007) Warburg, me and Hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39(3):211–222
Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P (2011) Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2:49. doi:10.3389/fphar.2011.00049
Qin J-Z, Nickoloff BJ (2010) 3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines. Biochem Biophys Res Commun 396:495–500
Ribeiro MJ, Almeida P, Strul D, Ferreira N, Loc’h C, Brulon V, Trébossen R, Mazière B, Bendriem B (1999) Comparison of fluorine-18 and bromine-76 imaging in positron emission tomography. Eur J Nucl Med 26(7):758–766
Soule HD, Vazquez J, Long A, Albert S, Brennan M (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51(5):1409–1416
Stockwin LH, Yu SX, Borgel S, Hancock C, Wolfe TL, Phillips LR, Hollingshead MG, Newton DL (2010) Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 127(11):2510–2519
Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260
Thangaraju M, Karunakaran SK, Itagaki S, Gopal E, Elangovan S, Prasad PD, Ganapathy V (2009) Transport via SLC5A8 with subsequent inhibition of histone deacetylases HDAC1 and HDAC3 underlies the antitumor activity of 3-Bromopyruvate. Cancer 115(20):4655–4666
Tsuchija S, Kobayashi Y, Goto Y, Okumura H, Nakae S, Konno T, Tada K (1982) Induction of maturation in cultured monocytic leukemia cells by a phorbol ester. Cancer Res 42:1530–1536
Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K (1980) Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 26:171–176
Warburg O, Wind F, Negelein E (1926) Ueber den Stoffwechsel von Tumoren im Körper. Klin Wochenschr 5:829–832
Yang Y, Cheng JZ, Singhal SS, Saini M, Pandya U, Awasthi S, Awasthi YC (2001) Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTH2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem 276:19220–19230
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Verhoeven, H.A., van Griensven, L.J.L.D. Flow cytometric evaluation of the effects of 3-bromopyruvate (3BP) and dichloracetate (DCA) on THP-1 cells: a multiparameter analysis. J Bioenerg Biomembr 44, 91–99 (2012). https://doi.org/10.1007/s10863-012-9414-7
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DOI: https://doi.org/10.1007/s10863-012-9414-7