Abstract
The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.
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References
Apfel MA, Ikeda BH, Speckhard DC, Frey PA (1984) Escherichia coli pyruvate dehydrogenase complex. Thiamin pyrophosphate-dependent inactivation by 3-bromopyruvate. J Biol Chem 259:2905–2909
Banas T, Gontero B, Drews VL, Johnson SL, Marcus F, Kemp RG (1988) Reactivity of the thiol groups of Escherichia coli phosphofructo-1-kinase. Biochim Biophys Acta 957:178–184
Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19:17–24
Dell’Antone P (2009) Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent. Med Chem 5:491–496
Ganapathy-Kanniappan S, Vali M, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Geschwind JF (2010a) 3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol 11:510–517
da Silva AP Pereira, El-Bacha T, Kyaw N, dos Santos RS, da-Silva WS, Almeida FC, Da Poian AT, Galina A (2009) Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate. Biochem J 417:717–726
Dell’Antone P (2006) Inactivation of H+-vacuolar ATPase by the energy blocker 3-bromopyruvate, a new antitumour agent. Life Sci 79:2049–2055
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 62:3909–3913
Ko YH, Pedersen PL, Geschwind JF (2001) Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett 173:83–91
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 324:269–275
Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786
Mathupala SP, Ko YH, Pedersen PL (2010) The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 1797:1225–1230
Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 31:227–285
Ramsay EE, Hogg PJ, Dilda PJ (2011) Mitochondrial metabolism inhibitors for cancer therapy. Pharm Res 28:2731–2744
Pastorino JG, Hoek JB (2003) Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem 10:1535–1551
Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25:4633–4646
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277
Shoshan-Barmatz V, Ben-Hail D: VDAC, a multi-functional mitochondrial protein as a pharmacological target, Mitochondrion 2011,
Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 1787:553–560
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 40:607–618
Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schagger H, Rustin P, Kroemer G (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689
Porter AG, Urbano AG (2006) Does apoptosis-inducing factor (AIF) have both life and death functions in cells? Bioessays 28:834–843
Joza N, Pospisilik JA, Hangen E, Hanada T, Modjtahedi N, Penninger JM, Kroemer G (2009) AIF: not just an apoptosis-inducing factor. Ann N Y Acad Sci 1171:2–11
Sevrioukova IF (2011) Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal 14:2545–2579
Penso J, Beitner R (1998) Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells. Eur J Pharmacol 342:113–117
Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16:819–830
Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E (2008) Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27:4636–4643
Pastorino JG, Shulga N, Hoek JB (2002) Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 277:7610–7618
Shulga N, Wilson-Smith R, Pastorino JG (2009) Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism. Cell Cycle 8:3355–3364
Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S (2007) Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer 120:175–180
Ihrlund LS, Hernlund E, Khan O, Shoshan MC (2008) 3-bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Molecular Oncology 2:94–101
Aram L, Geula S, Arbel N, Shoshan-Barmatz V (2010) VDAC1 cysteine residues: topology and function in channel activity and apoptosis. Biochem J 427:445–454
Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V (2008) Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem 283:13482–13490
Halestrap AP, McStay GP, Clarke SJ (2002) The permeability transition pore complex: another view. Biochimie 84:153–166
Costantini P, Belzacq AS, Vieira HL, Larochette N, de Pablo MA, Zamzami N, Susin SA, Brenner C, Kroemer G (2000) Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. Oncogene 19:307–314
Ganapathy-Kanniappan S, Geschwind JF, Kunjithapatham R, Buijs M, Vossen JA, Tchernyshyov I, Cole RN, Syed LH, Rao PP, Ota S, Vali M (2009) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death. Anticancer Res 29:4909–4918
Jones AR, Porter KE, Dobbie MS (1996) Renal and spermatozoal toxicity of alpha-bromohydrin, 3-bromolactate and 3-bromopyruvate. J Appl Toxicol 16:57–63
Sirover MA (2005) New nuclear functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. J Cell Biochem 95:45–52
Hara MR, Cascio MB, Sawa A (2006) GAPDH as a sensor of NO stress. Biochim Biophys Acta 1762:502–509
Yun SL, Suelter CH (1979) Modification of yeast pyruvate kinase by an active site-directed reagent, bromopyruvate. J Biol Chem 254:1811–1815
Acan NL, Ozer N (2001) Modification of human erythrocyte pyruvate kinase by an active site-directed reagent: bromopyruvate. J Enzyme Inhib 16:457–464
Ralph SJ, Rodriguez-Enriquez S, Neuzil J, Moreno-Sanchez R (2010) Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol Aspects Med 31:29–59
Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51
Pan JG, Mak TW: Metabolic targeting as an anticancer strategy: dawn of a new era?, Sci STKE 2007, 2007:pe14
Papandreou I, Goliasova T, Denko NC (2011) Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm? Int J Cancer 128:1001–1008
Korotchkina LG (1999) Showkat Ali M, Patel MS: Involvement of alpha-cysteine-62 and beta-tryptophan-135 in human pyruvate dehydrogenase catalysis. Arch Biochem Biophys 369:277–287
Kumar V, Kota V, Shivaji S (2008) Hamster sperm capacitation: role of pyruvate dehydrogenase A and dihydrolipoamide dehydrogenase. Biol Reprod 79:190–199
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942
Neuzil J, Dyason JC, Freeman R, Dong LF, Prochazka L, Wang XF, Scheffler I, Ralph SJ (2007) Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr 39:65–72
Qin JZ, Xin H, Nickoloff BJ (2010) 3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines. Biochem Biophys Res Commun 396:495–500
Macchioni L, Davidescu M, Sciaccaluga M, Marchetti C, Migliorati G, Coaccioli S, Roberti R, Corazzi L, Castigli E (2011) Mitochondrial dysfunction and effect of antiglycolytic bromopyruvic acid in GL15 glioblastoma cells. J Bioenerg Biomembr 43:507–518
White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15:5308–5316
Ganapathy-Kanniappan S, Geschwind JF, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Vali M (2010b) 3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines. Anticancer Res 30:923–935
Zhao H, Tanaka T, Halicka HD, Traganos F, Zarebski M, Dobrucki J, Darzynkiewicz Z (2007) Cytometric assessment of DNA damage by exogenous and endogenous oxidants reports aging-related processes. Cytometry A 71:905–914
Sanchez-Arago M, Cuezva JM (2011) 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 9:19
Nakano A, Tsuji D, Miki H, Cui Q, Sayed SM, Ikegame A, Oda A, Amou H, Nakamura S, Harada T, Fujii S, Kagawa K, Takeuchi K, Sakai A, Ozaki S, Okano K, Nakamura T, Itoh K, Matsumoto T, Abe M (2011) Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells. PLoS One 6:e27222
Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, Gao G, Zhang A, Xia X, Brasher H, Widger W, Ellis LM, Weihua Z: Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells, Cancer Res 2011
Cao X, Jia G, Zhang T, Yang M, Wang B, Wassenaar PA, Cheng H, Knopp MV, Sun D (2008) Non-invasive MRI tumor imaging and synergistic anticancer effect of HSP90 inhibitor and glycolysis inhibitor in RIP1-Tag2 transgenic pancreatic tumor model. Cancer Chemother Pharmacol 62:985–994
Pinheiro C, Longatto-Filho A, Pereira SM, Etlinger D, Moreira MA, Jube LF, Queiroz GS, Schmitt F, Baltazar F (2009) Monocarboxylate transporters 1 and 4 are associated with CD147 in cervical carcinoma. Dis Markers 26:97–103
Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F (2010) Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol 2010:427694
Chiche J, Brahimi-Horn MC, Pouyssegur J: Tumor hypoxia induces a metabolic shift causing acidosis: a common feature in cancer, J Cell Mol Med 2009
Le Floch R, Chiche J, Marchiq I, Naiken T, Ilk K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouyssegur J (2011) CD147 subunit of lactate/H + symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci U S A 108:16663–16668
Boidot R, Vegran F, Meulle A, Lebreton A, Dessy C, Sonveaux P, Lizard-Nacol S, Feron O: Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors, Cancer Res 2011
Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA Jr, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N (2009) Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325:1555–1559
Liapi E, Geschwind JF, Vali M, Khwaja AA, Prieto-Ventura V, Buijs M, Vossen JA, Ganapathy S, Wahl RL (2011) Assessment of tumoricidal efficacy and response to treatment with 18 F-FDG PET/CT after intraarterial infusion with the antiglycolytic agent 3-bromopyruvate in the VX2 model of liver tumor. J Nucl Med 52:225–230
Vali M, Vossen JA, Buijs M, Engles JM, Liapi E, Ventura VP, Khwaja A, Acha-Ngwodo O, Shanmugasundaram G, Syed L, Wahl RL, Geschwind JF (2008) Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study. J Pharmacol Exp Ther 327:32–37
Chang JM, Chung JW, Jae HJ, Eh H, Son KR, Lee KC, Park JH (2007) Local toxicity of hepatic arterial infusion of hexokinase II inhibitor, 3-bromopyruvate: In vivo investigation in normal rabbit model. Acad Radiol 14:85–92
Buijs M, Vossen JA, Geschwind JF, Ishimori T, Engles JM, Acha-Ngwodo O, Wahl RL, Vali M (2009) Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer. Invest New Drugs 27:120–123
Schaefer NG, Geschwind JF, Engles J, Buchanan JW, Wahl RL (2012) Systemic administration of 3-bromopyruvate in treating disseminated aggressive lymphoma. Transl Res 159:51–57
Smolkova K, Plecita-Hlavata L, Bellance N, Benard G, Rossignol R, Jezek P: Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells, Int J Biochem Cell Biol 2010
McCarty MF, Whitaker J (2010) Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev 15:264–272
Goodisman J, Hagrman D, Tacka KA, Souid AK (2006) Analysis of cytotoxicities of platinum compounds. Cancer Chemother Pharmacol 57:257–267
Custodio JB, Cardoso CM, Santos MS, Almeida LM, Vicente JA, Fernandes MA (2009) Cisplatin impairs rat liver mitochondrial functions by inducing changes on membrane ion permeability: prevention by thiol group protecting agents. Toxicology 259:18–24
Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V (2007) Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 226:157–167
Rybak LP (2007) Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 15:364–369
Kruidering M, Van de Water B, de Heer E, Mulder GJ, Nagelkerke JF (1997) Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp Ther 280:638–649
Santos NA, Catao CS, Martins NM, Curti C, Bianchi ML, Santos AC (2007) Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol 81:495–504
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Shoshan, M.C. 3-bromopyruvate: Targets and outcomes. J Bioenerg Biomembr 44, 7–15 (2012). https://doi.org/10.1007/s10863-012-9419-2
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DOI: https://doi.org/10.1007/s10863-012-9419-2