Journal of Cancer Research and Treatment
ISSN (Print): 2374-1996 ISSN (Online): 2374-2003 Website: Editor-in-chief: Jean Rommelaere
Open Access
Journal Browser
Journal of Cancer Research and Treatment. 2018, 6(1), 12-17
DOI: 10.12691/jcrt-6-1-3
Open AccessReview Article

3-bromopyruvate as a Promising Treatment for Hematological Cancer

Mongi Ayat1,

1Division of Hematology, Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

Pub. Date: March 06, 2018

Cite this paper:
Mongi Ayat. 3-bromopyruvate as a Promising Treatment for Hematological Cancer. Journal of Cancer Research and Treatment. 2018; 6(1):12-17. doi: 10.12691/jcrt-6-1-3


Many biological differences exist between cancer cells and normal cells that can act as potential targets in targeted cancer therapy. Hematological cancers e.g. lymphoma, leukemia and myeloma exhibit drug-resistance that ultimately results in deteriorated patients' conditions and high mortality rates. Resistance of hematological malignancy to conventional chemotherapy is attributed in part to upregulation of glucose oxidation (glycolysis) genes evidenced by gaining a promising chemosensitization effect upon adding a glycolysis inhibitor to chemotherapeutics. The promising anticancer agent 3-bromopyruvate (3BP) is a structural analog of both pyruvate and lactate. 3BP was reported to antagonize the Warburg effect (malignant phenotype where cancer cells utilize cytoplasmic glucose oxidation to produce ATP and lactate even in the presence of oxygen without making benefit of the generous ATP provision from glucose oxidation via mitochondrial pathways). Warburg effect deprives cancer cells from the high energetic yield achieved through utilizing mitochondrial pathways. 3BP is a promising antiglycolytic agent that targets major glycolysis enzymes (hexokinase II and glyceraldehyde-3-phosphate dehydrogenase. In this article, 3BP promising anticancer effects in treating lymphoma, leukemia and myeloma are discussed in addition to the mode of inhibition of Warburg effect using 3BP. In conclusion, 3BP is a promising anticancer drug (that will be more powerful upon proper pharmaceutical formulations) for treating hematological malignancies. 3BP is advisable to be included in treatment protocols in hematological cancers as a chemosensitizer or as a sole anticancer agent.

3-bromopyruvate lymphoma leukemia myeloma Warburg effect

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Baghdadi HH. Targeting cancer cells using 3-bromopyruvate for selective cancer treatment. Saudi J Med Med Sci. 2017, 5(1): 9-19.
[2]  Geschwind JF, Georgiades CS, Ko YH, Pedersen PL. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther 2004; 4: 449-57.
[3]  Ko YH, Pedersen PL, Geschwind JF. Glucose catabolism in the rabbit VX2 model for liver cancer. Cancer Lett 2001; 173: 83-91.
[4]  Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL. Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 2002; 62: 3909-13.
[5]  Schaefer NG, Geschwind JF, Engles J, Buchanan JW, Wahl RL. Systemic administration of 3-bromopyruvate in treating disseminated aggressive lymphoma. Transl Res. 2012 Jan; 159(1): 51-7.
[6]  Yadav S, Pandey SK, Kumar A, Kujur PK, Singh RP, Singh SM. Antitumor and chemosensitizing action of 3-bromopyruvate: Implication of deregulated metabolism. Chem Biol Interact. 2017 May 25; 270: 73-89.
[7]  Rodrigues AS, Pereira SL, Correia M, Gomes A, Perestrelo T, Ramalho-Santos J. Differentiate or Die: 3-Bromopyruvate and Pluripotency in Mouse Embryonic Stem Cells. PLoS One. 2015 Aug 12; 10(8): e0135617
[8]  Verhoeven HA, van Griensven LJ. Flow cytometric evaluation of the effects of 3-bromopyruvate (3BP) and dichloracetate (DCA) on THP-1 cells: a multiparameter analysis. J Bioenerg Biomembr. 2012 Feb; 44(1): 91-9.
[9]  Huang A, Ju HQ, Liu K, Zhan G, Liu D, Wen S, Garcia-Manero G, Huang P, Hu Y. Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation. Cancer Lett. 2016 Jul 28; 377(2): 149-57
[10]  Song K, Li M, Xu X, Xuan LI, Huang G, Liu Q. Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia. Oncol Lett. 2016 Jul; 12(1): 334-342
[11]  Calviño E, Estañ MC, Sánchez-Martín C, Brea R, de Blas E, Boyano-Adánez Mdel C, Rial E, Aller P. Regulation of death induction and chemosensitizing action of 3-bromopyruvate in myeloid leukemia cells: energy depletion, oxidative stress, and protein kinase activity modulation. J Pharmacol Exp Ther. 2014 Feb; 348(2): 324-35.
[12]  Hulleman E, Kazemier KM, Holleman A, VanderWeele DJ, Rudin CM, Broekhuis MJ, Evans WE, Pieters R, Den Boer ML. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood. 2009 Feb 26; 113(9): 2014-21.
[13]  Niedźwiecka K, Dyląg M, Augustyniak D, Majkowska-Skrobek G, Cal-Bąkowska M, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S. Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma. Oncotarget. 2016 Oct 4; 7(40): 65614-65626.
[14]  Nakano A, Miki H, Nakamura S, Harada T, Oda A, Amou H, Fujii S, Kagawa K, Takeuchi K, Ozaki S, Matsumoto T, Abe M. Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate. J Bioenerg Biomembr. 2012 Feb; 44(1): 31-8.
[15]  Cardone, R.A., Casavola, V., Reshkin, S.J. (2005). The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Reviews, Cancer, 5(10), 786-795.
[16]  Li, Y., Liu, L., Tollefsbol, T.O. (2010). Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. The FASEB Journal, 24(5), 1442-1453.
[17]  Meyerson, M., Counter, C., Eaton, E., Ellisen, L., Steiner, P., Caddle, S., et al. (1997). hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785-795.
[18]  Kanaya, T., Kyo, S., Takakura, M., Ito, H., Namiki, M., et al. (1998). hTERT is a critical determinant of telomerase activity in renal-cell carcinoma. International Journal of Cancer 78, 539-543
[19]  Gil, J., Peters, G. (2006). Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nature Reviews, Molecular Cell Biology, 7, 667-677.
[20]  Krishnamurthy, J., Torrice, C., Ramsey, M., Kovalev, G., Al-Regaiey, K., Su, L.,et al. (2004). Ink4a/Arf expression is a biomarker of aging. The Journal of Clinical Investigation, 114, 1299-1307.
[21]  Robert, K., Murray, Daryl, K., Granner, Peter, A., Mayes, & Victor. W. Rodwell. (2003). Harper’s illustrated biochemistry. (26th edition), Overview of Metabolism (pp. 122-127). Lange Medical Books/McGraw-Hill Medical Publishing Division
[22]  Thompson, C., Bauer, D., Lum, J., Hatzivassiliou, G., Zong, W., Zhao, F. et al (2005). How do cancer cells acquire the fuel needed to support cell growth? Cold Spring Harbor Symposia on Quantitative Biology, 70, 357-362.
[23]  Garber, K. (2006). Energy deregulation: licensing tumors to grow. Science, 312, 1158-1159.
[24]  Zhu, Z., Jiang, W., McGinley, J., Price, J., Gao, B., Thompson, H. (2007). Effects of dietary energy restriction on gene regulation in mammary epithelial cells. Cancer Research, 67, 12018-12025.
[25]  Hammerman, P., Fox, C., Thompson, C. (2004). Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends in Biochemical Sciences, 29, 586-592.
[26]  Skinner, R., Trujillo, A., Ma, X., Beierle, E.A. (2009). Ketone bodies inhibit the viability of human neuroblastoma cells. Journal of Pediatric Surgery, 44(1), 212-216.
[27]  Pereira da Silva AP, El-Bacha, T., Kyaw, N., dos Santos, R.S., da-Silva, W.S. et al. (2009). Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate. The Biochemical Journal, 417(3), 717-726.
[28]  Stubbs, M., McSheehy, P., M., Griffiths, J.R., Bashford, C.L. (2000). Causes and consequences of tumor acidity and implications for treatment. Molecular Medicine Today, 6(1), 15-19.
[29]  Colen, C.B., Shen, Y., Ghoddoussi, F., Yu, P., Francis, T.B., Koch, B.J., et al. (2011). Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study, Neoplasia, 13(7), 620-632.
[30]  Mulet, C., Lederer, F. (1977). Bromopyruvate as an affinity label for baker's yeast flavocytochrome b2. Kinetic study of the inactivation reaction. European Journal of Biochemistry, 73(2), 443-447.
[31]  Wahl, M.L., Owen, J.A., Burd, R., Herlands, R.A., Nogami, S.S., Rodeck, U., et al. (2002). Regulation of intracellular pH in human melanoma: potential therapeutic implications. Molecular Cancer Therapeutics, 1(8), 617-628.
[32]  Coss R.A., Storck, C.W., Daskalakis, C., Berd, D., Wahl, M.L. (2003). Intracellular acidification abrogates the heat shock response and compromises survival of human melanoma cells. Molecular Cancer Therapeutics, 2(4), 383-388.
[33]  Mathupala, S.P., Parajuli, P., Sloan, A.E. (2004). Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery, 55(6), 1410-1419.
[34]  Fantin, V.R., St-Pierre, J., Leder, P. (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell, 9(6), 425-434.
[35]  El Sayed, S.M., Abou El-Magd, R.M., Shishido, Y., Chung, S.P., Diem, T.H., Sakai, T., et al. (2012). 3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects. Journal of bioenergetics and biomembranes. In press.
[36]  Ko, Y.H., Smith, B.L., Wang, Y., Pomper, M.G., Rini, D.A., Torbenson, M.S., et al. (2004). Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochemical and Biophysical Research Communication, 324(1), 269-275.
[37]  Proskuryakov, S.Y., Konoplyannikov, A.G., Gabai, V.L. (2003). Necrosis: a specific form of programmed cell death? Experimental Cell Research, 283, 1-16.
[38]  Xu, R.H., Pelicano, H., Zhou, Y., Carew, J.S., Feng, L., Bhalla, K.N., et al. (2005). Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Research, 65(2), 613-621.
[39]  Dean, M. (2009). ABC transporters, drug resistance, and cancer stem cells. Journal of Mammary Gland Biology and Neoplasia, 14(1), 3-9.
[40]  Zhou, Y., Tozzi, F., Chen, J., Fan, F., Xia, L., Wang, J., et al. (2011). Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Research, in press.
[41]  Ihrlund, L.S., Hernlund, E., Khan, O., Shoshan, M.C. (2008). 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Molecular Oncology, 2(1), 94-101.
[42]  Akers, L.J., Fang, W., Levy, A.G., Franklin, A.R., Huang, P., Zweidler-McKay, P.A. (2011). Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. Leukemia Research, 35(6), 814-820.
[43]  Mathupala, S.P., Ko, Y.H., Pedersen, P.L. (2006) Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene, 25(34), 4777-4786.
[44]  Brosnan, J.T. (2001). Amino acids, then and now–a reflection on Sir Hans Krebs' contribution to nitrogen metabolism. IUBMB Life, 52, 265-270.
[45]  Zhang, X., Varin, E., Allouche, S., Lu, Y., Poulain, L., Icard, P. (2009). Effect of citrate on malignant pleural mesothelioma cells: a synergistic effect with cisplatin. Anticancer Research, 29(4), 1249-1254.
[46]  Halabe Bucay, A. (2009). Hypothesis proved...citric acid (citrate) does improve cancer: a case of a patient suffering from medullary thyroid cancer. Medical Hypotheses, 73(2), 271.
[47]  Lu, Y., Zhang, X., Zhang, H., Lan, J., Huang, G., Varin, E., et al. (2011). Citrate induces apoptotic cell death: a promising way to treat gastric carcinoma? Anticancer Research, 31(3), 797-805.
[48]  Nagoba, B.S., Punpale, A.S., Ayachit, R., Gandhi, R.C., Wadher, B.J. (2011). Citric acid treatment of postoperative wound in an operated case of synovial sarcoma of the knee. International Wound Journal, 8(4), 425-427.
[49]  Yousefi, S., Owens, J.W., Cesario, T.C. (2004). Citrate shows specific, dose-dependent lympholytic activity in neoplastic cell lines. Leukemia & Lymphoma, 45(8), 1657-1665.
[50]  Bogenrieder, T., Herlyn, M. (2003). Axis of evil: molecular mechanisms of cancer metastasis. Oncogene, 22(42):6524-6536.