Unravelling the Warburg effect: glycolytic inhibitors as promising agents in cancer therapy
DOI:
https://doi.org/10.48797/sl.2023.116Keywords:
tumor microenvironment, tumor metabolism, Warburg effect, glycolytic inhibitorsAbstract
The study of metabolic changes in cancer cells and their influence on tumor progression is still a challenge in oncobiology. Cancer cells are characterized by their high rates of glycolysis, even in the presence of oxygen, a phenomenon described as the Warburg effect. The increased glycolytic flux induces extracellular space acidification and boosts the more aggressive characteristics of cancer cells. Since monocarboxylate transporters, namely MCT1 and MCT4, play a role in the determination of intracellular pH, by exporting the accumulated lactic acid, they are upregulated in glycolytic tumors. Metabolic reprogramming emerged as an essential factor for cell survival and proliferation, also contributing to changes in the surrounding microenvironment, which often lead to resistance to antitumor compounds. Therefore, the altered metabolism can be an excellent target for new therapies in the cancer field, namely through the use of glycolytic inhibitors, which can inhibit cell metabolism and modify tumor microenvironment. 3-Bromopyruvate, 2-deoxyglucose and sodium dichloroacetate are able to alter the energy metabolism of cancer cells, either by acting directly on glycolysis or by redirecting pyruvate from glycolysis to the oxidative pathway. Here, we analyze how these glycolytic inhibitors interfere with tumor cell metabolism and, therefore, their potential use for new cancer therapeutic approaches.
References
Annibaldi, A.; Widmann, C. Glucose metabolism in cancer cells. Curr Opin Clin Nutr Metab Care 2010, 13, 466-470, doi:10.1097/MCO.0b013e32833a5577.
Mitchell, P.D.; Dittmar, J.M.; Mulder, B.; Inskip, S.; Littlewood, A.; Cessford, C.; Robb, J.E. The prevalence of cancer in Britain before industrialization. Cancer 2021, 127, 3054-3059, doi:10.1002/cncr.33615.
Qiu, H.; Cao, S.; Xu, R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond) 2021, 41, 1037-1048, doi:10.1002/cac2.12197.
Dyba, T.; Randi, G.; Bray, F.; Martos, C.; Giusti, F.; Nicholson, N.; Gavin, A.; Flego, M.; Neamtiu, L.; Dimitrova, N., et al. The European cancer burden in 2020: Incidence and mortality estimates for 40 countries and 25 major cancers. Eur J Cancer 2021, 157, 308-347, doi:10.1016/j.ejca.2021.07.039.
Fouad, Y.A.; Aanei, C. Revisiting the hallmarks of cancer. Am J Cancer Res 2017, 7, 1016-1036.
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57-70, doi:10.1016/s0092-8674(00)81683-9.
Senga, S.S.; Grose, R.P. Hallmarks of cancer-the new testament. Open Biol 2021, 11, 200358, doi:10.1098/rsob.200358.
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 2011, 144, 646-674, doi:10.1016/j.cell.2011.02.013.
Hanahan, D. Hallmarks of Cancer: New Dimensions. Cancer Discov 2022, 12, 31-46, doi:10.1158/2159-8290.CD-21-1059.
Vanhove, K.; Graulus, G.J.; Mesotten, L.; Thomeer, M.; Derveaux, E.; Noben, J.P.; Guedens, W.; Adriaensens, P. The Metabolic Landscape of Lung Cancer: New Insights in a Disturbed Glucose Metabolism. Front Oncol 2019, 9, 1215, doi:10.3389/fonc.2019.01215.
Martinez-Outschoorn, U.E.; Peiris-Pages, M.; Pestell, R.G.; Sotgia, F.; Lisanti, M.P. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 2017, 14, 11-31, doi:10.1038/nrclinonc.2016.60.
Xia, L.; Oyang, L.; Lin, J.; Tan, S.; Han, Y.; Wu, N.; Yi, P.; Tang, L.; Pan, Q.; Rao, S., et al. The cancer metabolic reprogramming and immune response. Mol Cancer 2021, 20, 28, doi:10.1186/s12943-021-01316-8.
Wong, K.K.L.; Verheyen, E.M. Metabolic reprogramming in cancer: mechanistic insights from Drosophila. Dis Model Mech 2021, 14, 1-17, doi:10.1242/dmm.048934.
Wang, Z.H.; Peng, W.B.; Zhang, P.; Yang, X.P.; Zhou, Q. Lactate in the tumour microenvironment: From immune modulation to therapy. EBioMedicine 2021, 73, 103627, doi:10.1016/j.ebiom.2021.103627.
Gyamfi, J.; Kim, J.; Choi, J. Cancer as a Metabolic Disorder. Int J Mol Sci 2022, 23, doi:10.3390/ijms23031155.
Li, H.; Ning, S.; Ghandi, M.; Kryukov, G.V.; Gopal, S.; Deik, A.; Souza, A.; Pierce, K.; Keskula, P.; Hernandez, D., et al. The landscape of cancer cell line metabolism. Nat Med 2019, 25, 850-860, doi:10.1038/s41591-019-0404-8.
Akins, N.S.; Nielson, T.C.; Le, H.V. Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer. Curr Top Med Chem 2018, 18, 494-504, doi:10.2174/1568026618666180523111351.
Corsale, A.M.; Di Simone, M.; Lo Presti, E.; Picone, C.; Dieli, F.; Meraviglia, S. Metabolic Changes in Tumor Microenvironment: How Could They Affect gammadelta T Cells Functions? Cells 2021, 10, doi:10.3390/cells10112896.
Bouillaud, F.; Hammad, N.; Schwartz, L. Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters. Biology (Basel) 2021, 10, doi:10.3390/biology10101000.
Pascale, R.M.; Calvisi, D.F.; Simile, M.M.; Feo, C.F.; Feo, F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel) 2020, 12, doi:10.3390/cancers12102819.
Poff, A.; Koutnik, A.P.; Egan, K.M.; Sahebjam, S.; D'Agostino, D.; Kumar, N.B. Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma. Semin Cancer Biol 2019, 56, 135-148, doi:10.1016/j.semcancer.2017.12.011.
Orang, A.V.; Petersen, J.; McKinnon, R.A.; Michael, M.Z. Micromanaging aerobic respiration and glycolysis in cancer cells. Mol Metab 2019, 23, 98-126, doi:10.1016/j.molmet.2019.01.014.
Ahmad, F.; Cherukuri, M.K.; Choyke, P.L. Metabolic reprogramming in prostate cancer. Br J Cancer 2021, 125, 1185-1196, doi:10.1038/s41416-021-01435-5.
Padda, J.; Khalid, K.; Kakani, V.; Cooper, A.C.; Jean-Charles, G. Metabolic Acidosis in Leukemia. Cureus 2021, 13, e17732, doi:10.7759/cureus.17732.
Romero-Garcia, S.; Moreno-Altamirano, M.M.; Prado-Garcia, H.; Sanchez-Garcia, F.J. Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front Immunol 2016, 7, 52, doi:10.3389/fimmu.2016.00052.
Wilde, L.; Roche, M.; Domingo-Vidal, M.; Tanson, K.; Philp, N.; Curry, J.; Martinez-Outschoorn, U. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin Oncol 2017, 44, 198-203, doi:10.1053/j.seminoncol.2017.10.004.
Chandel, V.; Maru, S.; Kumar, A.; Kumar, A.; Sharma, A.; Rathi, B.; Kumar, D. Role of monocarboxylate transporters in head and neck squamous cell carcinoma. Life Sci 2021, 279, 119709, doi:10.1016/j.lfs.2021.119709.
Payen, V.L.; Mina, E.; Van Hee, V.F.; Porporato, P.E.; Sonveaux, P. Monocarboxylate transporters in cancer. Mol Metab 2020, 33, 48-66, doi:10.1016/j.molmet.2019.07.006.
Fisel, P.; Schaeffeler, E.; Schwab, M. Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy. Clin Transl Sci 2018, 11, 352-364, doi:10.1111/cts.12551.
Eilertsen, M.; Andersen, S.; Al-Saad, S.; Kiselev, Y.; Donnem, T.; Stenvold, H.; Pettersen, I.; Al-Shibli, K.; Richardsen, E.; Busund, L.T., et al. Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival. PLoS One 2014, 9, e105038, doi:10.1371/journal.pone.0105038.
Jones, R.S.; Parker, M.D.; Morris, M.E. Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F2alpha: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model. Pharmaceutics 2020, 12, doi:10.3390/pharmaceutics12030201.
Jones, R.S.; Morris, M.E. Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease. Clin Pharmacol Ther 2016, 100, 454-463, doi:10.1002/cpt.418.
Azevedo-Silva, J.; Queiros, O.; Baltazar, F.; Ulaszewski, S.; Goffeau, A.; Ko, Y.H.; Pedersen, P.L.; Preto, A.; Casal, M. The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. J Bioenerg Biomembr 2016, 48, 349-362, doi:10.1007/s10863-016-9670-z.
Sun, X.; Wang, M.; Wang, M.; Yao, L.; Li, X.; Dong, H.; Li, M.; Sun, T.; Liu, X.; Liu, Y., et al. Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential. Front Cell Dev Biol 2020, 8, 651, doi:10.3389/fcell.2020.00651.
Johnson, J.M.; Cotzia, P.; Fratamico, R.; Mikkilineni, L.; Chen, J.; Colombo, D.; Mollaee, M.; Whitaker-Menezes, D.; Domingo-Vidal, M.; Lin, Z., et al. MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer. Front Cell Dev Biol 2017, 5, 27, doi:10.3389/fcell.2017.00027.
Payen, V.L.; Hsu, M.Y.; Radecke, K.S.; Wyart, E.; Vazeille, T.; Bouzin, C.; Porporato, P.E.; Sonveaux, P. Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter. Cancer Res 2017, 77, 5591-5601, doi:10.1158/0008-5472.CAN-17-0764.
Lee, G.H.; Kim, D.S.; Chung, M.J.; Chae, S.W.; Kim, H.R.; Chae, H.J. Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved. Oncol Lett 2011, 2, 831-838, doi:10.3892/ol.2011.353.
Pinheiro, C.; Miranda-Goncalves, V.; Longatto-Filho, A.; Vicente, A.L.; Berardinelli, G.N.; Scapulatempo-Neto, C.; Costa, R.F.; Viana, C.R.; Reis, R.M.; Baltazar, F., et al. The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4. Cell Cycle 2016, 15, 1462-1470, doi:10.1080/15384101.2016.1175258.
Ho, J.; de Moura, M.B.; Lin, Y.; Vincent, G.; Thorne, S.; Duncan, L.M.; Hui-Min, L.; Kirkwood, J.M.; Becker, D.; Van Houten, B., et al. Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol Cancer 2012, 11, 76, doi:10.1186/1476-4598-11-76.
Quanz, M.; Bender, E.; Kopitz, C.; Grunewald, S.; Schlicker, A.; Schwede, W.; Eheim, A.; Toschi, L.; Neuhaus, R.; Richter, C., et al. Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance. Mol Cancer Ther 2018, 17, 2285-2296, doi:10.1158/1535-7163.MCT-17-1253.
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., et al. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat Genet 2013, 45, 104-108, doi:10.1038/ng.2471.
Spinello, I.; Saulle, E.; Quaranta, M.T.; Pasquini, L.; Pelosi, E.; Castelli, G.; Ottone, T.; Voso, M.T.; Testa, U.; Labbaye, C. The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells. Haematologica 2019, 104, 973-985, doi:10.3324/haematol.2018.199661.
Xu, J.; Shen, Z.Y.; Chen, X.G.; Zhang, Q.; Bian, H.J.; Zhu, P.; Xu, H.Y.; Song, F.; Yang, X.M.; Mi, L., et al. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 2007, 45, 269-276, doi:10.1002/hep.21465.
Bian, H.; Zheng, J.S.; Nan, G.; Li, R.; Chen, C.; Hu, C.X.; Zhang, Y.; Sun, B.; Wang, X.L.; Cui, S.C., et al. Randomized trial of [131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation. J Natl Cancer Inst 2014, 106, doi:10.1093/jnci/dju239.
Fan, X.Y.; He, D.; Sheng, C.B.; Wang, B.; Wang, L.J.; Wu, X.Q.; Xu, L.; Jiang, J.L.; Li, L.; Chen, Z.N. Therapeutic anti-CD147 antibody sensitizes cells to chemoradiotherapy via targeting pancreatic cancer stem cells. Am J Transl Res 2019, 11, 3543-3554.
Landras, A.; Reger de Moura, C.; Jouenne, F.; Lebbe, C.; Menashi, S.; Mourah, S. CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker. Cancers (Basel) 2019, 11, doi:10.3390/cancers11111803.
Pereira-Nunes, A.; Ferreira, H.; Abreu, S.; Guedes, M.; Neves, N.M.; Baltazar, F.; Granja, S. Combination Therapy With CD147-Targeted Nanoparticles Carrying Phenformin Decreases Lung Cancer Growth. Adv Biol (Weinh) 2023, 7, e2300080, doi:10.1002/adbi.202300080.
Yu, W.; Lei, Q.; Yang, L.; Qin, G.; Liu, S.; Wang, D.; Ping, Y.; Zhang, Y. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol 2021, 14, 187, doi:10.1186/s13045-021-01200-4.
Zaal, E.A.; Berkers, C.R. The Influence of Metabolism on Drug Response in Cancer. Front Oncol 2018, 8, 500, doi:10.3389/fonc.2018.00500.
Reina-Campos, M.; Moscat, J.; Diaz-Meco, M. Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol 2017, 48, 47-53, doi:10.1016/j.ceb.2017.05.006.
Gouirand, V.; Guillaumond, F.; Vasseur, S. Influence of the Tumor Microenvironment on Cancer Cells Metabolic Reprogramming. Front Oncol 2018, 8, 117, doi:10.3389/fonc.2018.00117.
Li, J.; Eu, J.Q.; Kong, L.R.; Wang, L.; Lim, Y.C.; Goh, B.C.; Wong, A.L.A. Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy. Molecules 2020, 25, doi:10.3390/molecules25204831.
Danhier, P.; Banski, P.; Payen, V.L.; Grasso, D.; Ippolito, L.; Sonveaux, P.; Porporato, P.E. Cancer metabolism in space and time: Beyond the Warburg effect. Biochim Biophys Acta Bioenerg 2017, 1858, 556-572, doi:10.1016/j.bbabio.2017.02.001.
Biswas, S.K. Metabolic Reprogramming of Immune Cells in Cancer Progression. Immunity 2015, 43, 435-449, doi:10.1016/j.immuni.2015.09.001.
Cameron, M.E.; Yakovenko, A.; Trevino, J.G. Glucose and Lactate Transport in Pancreatic Cancer: Glycolytic Metabolism Revisited. J Oncol 2018, 2018, 6214838, doi:10.1155/2018/6214838.
Goswami, K.K.; Ghosh, T.; Ghosh, S.; Sarkar, M.; Bose, A.; Baral, R. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol 2017, 316, 1-10, doi:10.1016/j.cellimm.2017.04.005.
Paredes, F.; Williams, H.C.; San Martin, A. Metabolic adaptation in hypoxia and cancer. Cancer Lett 2021, 502, 133-142, doi:10.1016/j.canlet.2020.12.020.
Fu, Y.; Liu, S.; Yin, S.; Niu, W.; Xiong, W.; Tan, M.; Li, G.; Zhou, M. The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy. Oncotarget 2017, 8, 57813-57825, doi:10.18632/oncotarget.18175.
Pinheiro, C.; Longatto-Filho, A.; Azevedo-Silva, J.; Casal, M.; Schmitt, F.C.; Baltazar, F. Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 2012, 44, 127-139, doi:10.1007/s10863-012-9428-1.
Al Tameemi, W.; Dale, T.P.; Al-Jumaily, R.M.K.; Forsyth, N.R. Hypoxia-Modified Cancer Cell Metabolism. Front Cell Dev Biol 2019, 7, 4, doi:10.3389/fcell.2019.00004.
Vaupel, P.; Harrison, L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 2004, 9 Suppl 5, 4-9, doi:10.1634/theoncologist.9-90005-4.
Tataranni, T.; Piccoli, C. Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications. Oxid Med Cell Longev 2019, 2019, 8201079, doi:10.1155/2019/8201079.
Lee, T.G.; Jeong, E.H.; Min, I.J.; Kim, S.Y.; Kim, H.R.; Kim, C.H. Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors. Oncol Lett 2017, 14, 2191-2197, doi:10.3892/ol.2017.6428.
Sun, H.; Zhu, A.; Zhou, X.; Wang, F. Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. Oncotarget 2017, 8, 52642-52650, doi:10.18632/oncotarget.16991.
Wojtkowiak, J.W.; Verduzco, D.; Schramm, K.J.; Gillies, R.J. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm 2011, 8, 2032-2038, doi:10.1021/mp200292c.
Vukovic, V.; Tannock, I.F. Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer 1997, 75, 1167-1172, doi:10.1038/bjc.1997.201.
Catanzaro, D.; Gaude, E.; Orso, G.; Giordano, C.; Guzzo, G.; Rasola, A.; Ragazzi, E.; Caparrotta, L.; Frezza, C.; Montopoli, M. Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. Oncotarget 2015, 6, 30102-30114, doi:10.18632/oncotarget.4945.
Voss, M.; Lorenz, N.I.; Luger, A.L.; Steinbach, J.P.; Rieger, J.; Ronellenfitsch, M.W. Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet. Int J Mol Sci 2018, 19, doi:10.3390/ijms19082462.
Gu, Q.L.; Zhang, Y.; Fu, X.M.; Lu, Z.L.; Yu, Y.; Chen, G.; Ma, R.; Kou, W.; Lan, Y.M. Toxicity and metabolism of 3-bromopyruvate in Caenorhabditis elegans. J Zhejiang Univ Sci B 2020, 21, 77-86, doi:10.1631/jzus.B1900370.
Calvino, E.; Estan, M.C.; Sanchez-Martin, C.; Brea, R.; de Blas, E.; Boyano-Adanez 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, 348, 324-335, doi:10.1124/jpet.113.206714.
Baghdadi, H.H. Targeting Cancer Cells using 3-bromopyruvate for Selective Cancer Treatment. Saudi J Med Med Sci 2017, 5, 9-19, doi:10.4103/1658-631X.194253.
Azevedo-Silva, J.; Queiros, O.; Ribeiro, A.; Baltazar, F.; Young, K.H.; Pedersen, P.L.; Preto, A.; Casal, M. The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH. Biochem J 2015, 467, 247-258, doi:10.1042/BJ20140921.
Guo, C.; Liu, S.; Sun, M.Z. Novel insight into the role of GAPDH playing in tumor. Clin Transl Oncol 2013, 15, 167-172, doi:10.1007/s12094-012-0924-x.
Higashimura, Y.; Nakajima, Y.; Yamaji, R.; Harada, N.; Shibasaki, F.; Nakano, Y.; Inui, H. Up-regulation of glyceraldehyde-3-phosphate dehydrogenase gene expression by HIF-1 activity depending on Sp1 in hypoxic breast cancer cells. Arch Biochem Biophys 2011, 509, 1-8, doi:10.1016/j.abb.2011.02.011.
Ganapathy-Kanniappan, S.; Kunjithapatham, R.; Geschwind, J.F. Anticancer efficacy of the metabolic blocker 3-bromopyruvate: specific molecular targeting. Anticancer Res 2013, 33, 13-20.
Ganapathy-Kanniappan, S.; Vali, M.; Kunjithapatham, R.; Buijs, M.; Syed, L.H.; Rao, P.P.; Ota, S.; Kwak, B.K.; Loffroy, R.; Geschwind, J.F. 3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol 2010, 11, 510-517, doi:10.2174/138920110791591427.
Tang, Z.; Yuan, S.; Hu, Y.; Zhang, H.; Wu, W.; Zeng, Z.; Yang, J.; Yun, J.; Xu, R.; Huang, P. Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester. J Bioenerg Biomembr 2012, 44, 117-125, doi:10.1007/s10863-012-9420-9.
El Sayed, S.M.; Abou El-Magd, R.M.; Shishido, Y.; Chung, S.P.; Sakai, T.; Watanabe, H.; Kagami, S.; Fukui, K. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate. Cancer Gene Ther 2012, 19, 1-18, doi:10.1038/cgt.2011.59.
Dell'Antone, P. Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent. Med Chem 2009, 5, 491-496, doi:10.2174/157340609790170551.
Jardim-Messeder, D.; Moreira-Pacheco, F. 3-Bromopyruvic Acid Inhibits Tricarboxylic Acid Cycle and Glutaminolysis in HepG2 Cells. Anticancer Res 2016, 36, 2233-2241.
Xiao, H.; Li, S.; Zhang, D.; Liu, T.; Yu, M.; Wang, F. Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate in pancreatic cancer cells. Oncol Rep 2013, 29, 329-334, doi:10.3892/or.2012.2085.
Nakano, A.; Tsuji, D.; Miki, H.; Cui, Q.; El Sayed, S.M.; Ikegame, A.; Oda, A.; Amou, H.; Nakamura, S.; Harada, T., et al. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells. PLoS One 2011, 6, e27222, doi:10.1371/journal.pone.0027222.
Wu, L.; Xu, J.; Yuan, W.; Wu, B.; Wang, H.; Liu, G.; Wang, X.; Du, J.; Cai, S. The reversal effects of 3-bromopyruvate on multidrug resistance in vitro and in vivo derived from human breast MCF-7/ADR cells. PLoS One 2014, 9, e112132, doi:10.1371/journal.pone.0112132.
Ko, Y.H.; Smith, B.L.; Wang, Y.; Pomper, M.G.; Rini, D.A.; Torbenson, M.S.; Hullihen, J.; Pedersen, P.L. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004, 324, 269-275, doi:10.1016/j.bbrc.2004.09.047.
Lee, K.H.; Park, J.H.; Won, R.; Lee, H.; Nam, T.S.; Lee, B.H. Inhibition of hexokinase leads to neuroprotection against excitotoxicity in organotypic hippocampal slice culture. J Neurosci Res 2011, 89, 96-107, doi:10.1002/jnr.22525.
Faubert, B.; Li, K.Y.; Cai, L.; Hensley, C.T.; Kim, J.; Zacharias, L.G.; Yang, C.; Do, Q.N.; Doucette, S.; Burguete, D., et al. Lactate Metabolism in Human Lung Tumors. Cell 2017, 171, 358-371 e359, doi:10.1016/j.cell.2017.09.019.
Ko, Y.H.; Verhoeven, H.A.; Lee, M.J.; Corbin, D.J.; Vogl, T.J.; Pedersen, P.L. A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr 2012, 44, 163-170, doi:10.1007/s10863-012-9417-4.
El Sayed, S.M.; Mohamed, W.G.; Seddik, M.A.; Ahmed, A.S.; Mahmoud, A.G.; Amer, W.H.; Helmy Nabo, M.M.; Hamed, A.R.; Ahmed, N.S.; Abd-Allah, A.A. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin J Cancer 2014, 33, 356-364, doi:10.5732/cjc.013.10111.
Moreno-Sanchez, R.; Rodriguez-Enriquez, S.; Marin-Hernandez, A.; Saavedra, E. Energy metabolism in tumor cells. FEBS J 2007, 274, 1393-1418, doi:10.1111/j.1742-4658.2007.05686.x.
Kho, A.R.; Choi, B.Y.; Lee, S.H.; Hong, D.K.; Jeong, J.H.; Kang, B.S.; Kang, D.H.; Park, K.H.; Park, J.B.; Suh, S.W. The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury. Cells 2019, 8, doi:10.3390/cells8050405.
Michelakis, E.D.; Webster, L.; Mackey, J.R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 2008, 99, 989-994, doi:10.1038/sj.bjc.6604554.
Babu, E.; Ramachandran, S.; CoothanKandaswamy, V.; Elangovan, S.; Prasad, P.D.; Ganapathy, V.; Thangaraju, M. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene 2011, 30, 4026-4037, doi:10.1038/onc.2011.113.
Jackson, V.N.; Halestrap, A.P. 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(carboxyethyl)-5(6)-carboxyfluorescein. J Biol Chem 1996, 271, 861-868, doi:10.1074/jbc.271.2.861.
Kwak, C.H.; Jin, L.; Han, J.H.; Han, C.W.; Kim, E.; Cho, M.; Chung, T.W.; Bae, S.J.; Jang, S.B.; Ha, K.T. Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity. Int J Mol Sci 2020, 21, doi:10.3390/ijms21176021.
Vella, S.; Conti, M.; Tasso, R.; Cancedda, R.; Pagano, A. Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. Int J Cancer 2012, 130, 1484-1493, doi:10.1002/ijc.26173.
Liang, Y.; Hou, L.; Li, L.; Li, L.; Zhu, L.; Wang, Y.; Huang, X.; Hou, Y.; Zhu, D.; Zou, H., et al. Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway. Oncogene 2020, 39, 469-485, doi:10.1038/s41388-019-1035-8.
Kaplon, J.; Zheng, L.; Meissl, K.; Chaneton, B.; Selivanov, V.A.; Mackay, G.; van der Burg, S.H.; Verdegaal, E.M.; Cascante, M.; Shlomi, T., et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 2013, 498, 109-112, doi:10.1038/nature12154.
Kim, T.S.; Lee, M.; Park, M.; Kim, S.Y.; Shim, M.S.; Lee, C.Y.; Choi, D.H.; Cho, Y. Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1. Int J Mol Sci 2021, 22, doi:10.3390/ijms221810027.
Skeberdyte, A.; Sarapiniene, I.; Aleksander-Krasko, J.; Stankevicius, V.; Suziedelis, K.; Jarmalaite, S. Dichloroacetate and Salinomycin Exert a Synergistic Cytotoxic Effect in Colorectal Cancer Cell Lines. Sci Rep 2018, 8, 17744, doi:10.1038/s41598-018-35815-4.
Florio, R.; De Lellis, L.; Veschi, S.; Verginelli, F.; di Giacomo, V.; Gallorini, M.; Perconti, S.; Sanna, M.; Mariani-Costantini, R.; Natale, A., et al. Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells. Sci Rep 2018, 8, 13610, doi:10.1038/s41598-018-31797-5.
Sun, R.C.; Fadia, M.; Dahlstrom, J.E.; Parish, C.R.; Board, P.G.; Blackburn, A.C. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 2010, 120, 253-260, doi:10.1007/s10549-009-0435-9.
Rajeshkumar, N.V.; Yabuuchi, S.; Pai, S.G.; De Oliveira, E.; Kamphorst, J.J.; Rabinowitz, J.D.; Tejero, H.; Al-Shahrour, F.; Hidalgo, M.; Maitra, A., et al. Treatment of Pancreatic Cancer Patient-Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin. Clin Cancer Res 2017, 23, 5639-5647, doi:10.1158/1078-0432.CCR-17-1115.
Bonnet, S.; Archer, S.L.; Allalunis-Turner, J.; Haromy, A.; Beaulieu, C.; Thompson, R.; Lee, C.T.; Lopaschuk, G.D.; Puttagunta, L.; Bonnet, S., et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007, 11, 37-51, doi:10.1016/j.ccr.2006.10.020.
Garon, E.B.; Christofk, H.R.; Hosmer, W.; Britten, C.D.; Bahng, A.; Crabtree, M.J.; Hong, C.S.; Kamranpour, N.; Pitts, S.; Kabbinavar, F., et al. Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer. J Cancer Res Clin Oncol 2014, 140, 443-452, doi:10.1007/s00432-014-1583-9.
Chu, Q.S.; Sangha, R.; Spratlin, J.; Vos, L.J.; Mackey, J.R.; McEwan, A.J.; Venner, P.; Michelakis, E.D. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest New Drugs 2015, 33, 603-610, doi:10.1007/s10637-015-0221-y.
Dunbar, E.M.; Coats, B.S.; Shroads, A.L.; Langaee, T.; Lew, A.; Forder, J.R.; Shuster, J.J.; Wagner, D.A.; Stacpoole, P.W. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs 2014, 32, 452-464, doi:10.1007/s10637-013-0047-4.
Xuan, Y.; Hur, H.; Ham, I.H.; Yun, J.; Lee, J.Y.; Shim, W.; Kim, Y.B.; Lee, G.; Han, S.U.; Cho, Y.K. Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism. Exp Cell Res 2014, 321, 219-230, doi:10.1016/j.yexcr.2013.12.009.
Stockwin, L.H.; Yu, S.X.; Borgel, S.; Hancock, C.; Wolfe, T.L.; Phillips, L.R.; Hollingshead, M.G.; Newton, D.L. Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 2010, 127, 2510-2519, doi:10.1002/ijc.25499.
Pajak, B.; Siwiak, E.; Soltyka, M.; Priebe, A.; Zielinski, R.; Fokt, I.; Ziemniak, M.; Jaskiewicz, A.; Borowski, R.; Domoradzki, T., et al. 2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents. Int J Mol Sci 2019, 21, doi:10.3390/ijms21010234.
Aft, R.L.; Zhang, F.W.; Gius, D. Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer 2002, 87, 805-812, doi:10.1038/sj.bjc.6600547.
Korga, A.; Ostrowska, M.; Iwan, M.; Herbet, M.; Dudka, J. Inhibition of glycolysis disrupts cellular antioxidant defense and sensitizes HepG2 cells to doxorubicin treatment. FEBS Open Bio 2019, 9, 959-972, doi:10.1002/2211-5463.12628.
Xi, H.; Kurtoglu, M.; Lampidis, T.J. The wonders of 2-deoxy-D-glucose. IUBMB Life 2014, 66, 110-121, doi:10.1002/iub.1251.
Lee, N.; Jang, W.J.; Seo, J.H.; Lee, S.; Jeong, C.H. 2-Deoxy-d-Glucose-Induced Metabolic Alteration in Human Oral Squamous SCC15 Cells: Involvement of N-Glycosylation of Axl and Met. Metabolites 2019, 9, doi:10.3390/metabo9090188.
Kurtoglu, M.; Gao, N.; Shang, J.; Maher, J.C.; Lehrman, M.A.; Wangpaichitr, M.; Savaraj, N.; Lane, A.N.; Lampidis, T.J. Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. Mol Cancer Ther 2007, 6, 3049-3058, doi:10.1158/1535-7163.MCT-07-0310.
Repas, J.; Zugner, E.; Gole, B.; Bizjak, M.; Potocnik, U.; Magnes, C.; Pavlin, M. Metabolic profiling of attached and detached metformin and 2-deoxy-D-glucose treated breast cancer cells reveals adaptive changes in metabolome of detached cells. Sci Rep 2021, 11, 21354, doi:10.1038/s41598-021-98642-0.
Sandulache, V.C.; Ow, T.J.; Pickering, C.R.; Frederick, M.J.; Zhou, G.; Fokt, I.; Davis-Malesevich, M.; Priebe, W.; Myers, J.N. Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. Cancer 2011, 117, 2926-2938, doi:10.1002/cncr.25868.
Pietzke, M.; Zasada, C.; Mudrich, S.; Kempa, S. Decoding the dynamics of cellular metabolism and the action of 3-bromopyruvate and 2-deoxyglucose using pulsed stable isotope-resolved metabolomics. Cancer Metab 2014, 2, 9, doi:10.1186/2049-3002-2-9.
De Bock, K.; Georgiadou, M.; Schoors, S.; Kuchnio, A.; Wong, B.W.; Cantelmo, A.R.; Quaegebeur, A.; Ghesquiere, B.; Cauwenberghs, S.; Eelen, G., et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 2013, 154, 651-663, doi:10.1016/j.cell.2013.06.037.
Sottnik, J.L.; Lori, J.C.; Rose, B.J.; Thamm, D.H. Glycolysis inhibition by 2-deoxy-D-glucose reverts the metastatic phenotype in vitro and in vivo. Clin Exp Metastasis 2011, 28, 865-875, doi:10.1007/s10585-011-9417-5.
DiPaola, R.S.; Dvorzhinski, D.; Thalasila, A.; Garikapaty, V.; Doram, D.; May, M.; Bray, K.; Mathew, R.; Beaudoin, B.; Karp, C., et al. Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy. Prostate 2008, 68, 1743-1752, doi:10.1002/pros.20837.
Wu, H.; Zhu, H.; Liu, D.X.; Niu, T.K.; Ren, X.; Patel, R.; Hait, W.N.; Yang, J.M. Silencing of elongation factor-2 kinase potentiates the effect of 2-deoxy-D-glucose against human glioma cells through blunting of autophagy. Cancer Res 2009, 69, 2453-2460, doi:10.1158/0008-5472.CAN-08-2872.
Cunha, A.; Rocha, A.C.; Barbosa, F.; Baiao, A.; Silva, P.; Sarmento, B.; Queiros, O. Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model. Pharmaceutics 2022, 14, doi:10.3390/pharmaceutics14102021.
Stein, M.; Lin, H.; Jeyamohan, C.; Dvorzhinski, D.; Gounder, M.; Bray, K.; Eddy, S.; Goodin, S.; White, E.; Dipaola, R.S. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010, 70, 1388-1394, doi:10.1002/pros.21172.
Mohanti, B.K.; Rath, G.K.; Anantha, N.; Kannan, V.; Das, B.S.; Chandramouli, B.A.; Banerjee, A.K.; Das, S.; Jena, A.; Ravichandran, R., et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys 1996, 35, 103-111, doi:10.1016/s0360-3016(96)85017-6.
Raez, L.E.; Papadopoulos, K.; Ricart, A.D.; Chiorean, E.G.; Dipaola, R.S.; Stein, M.N.; Rocha Lima, C.M.; Schlesselman, J.J.; Tolba, K.; Langmuir, V.K., et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 2013, 71, 523-530, doi:10.1007/s00280-012-2045-1.
Hansen, I.L.; Levy, M.M.; Kerr, D.S. The 2-deoxyglucose test as a supplement to fasting for detection of childhood hypoglycemia. Pediatr Res 1984, 18, 490-495, doi:10.1203/00006450-198405000-00020.
Fan, T.; Sun, G.; Sun, X.; Zhao, L.; Zhong, R.; Peng, Y. Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment. Cancers (Basel) 2019, 11, doi:10.3390/cancers11030317.
Abbaszadeh, H.; Valizadeh, A.; Mahdavinia, M.; Teimoori, A.; Pipelzadeh, M.H.; Zeidooni, L.; Alboghobeish, S. 3-Bromopyruvate potentiates TRAIL-induced apoptosis in human colon cancer cells through a reactive oxygen species- and caspase-dependent mitochondrial pathway. Can J Physiol Pharmacol 2019, 97, 1176-1184, doi:10.1139/cjpp-2019-0131.
Cao, X.; Bloomston, M.; Zhang, T.; Frankel, W.L.; Jia, G.; Wang, B.; Hall, N.C.; Koch, R.M.; Cheng, H.; Knopp, M.V., et al. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin Cancer Res 2008, 14, 1831-1839, doi:10.1158/1078-0432.CCR-07-1607.
Lu, X.; Zhou, D.; Hou, B.; Liu, Q.X.; Chen, Q.; Deng, X.F.; Yu, Z.B.; Dai, J.G.; Zheng, H. Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer. Cancer Manag Res 2018, 10, 1231-1241, doi:10.2147/CMAR.S156530.
Xie, Q.; Zhang, H.F.; Guo, Y.Z.; Wang, P.Y.; Liu, Z.S.; Gao, H.D.; Xie, W.L. Combination of Taxol(R) and dichloroacetate results in synergistically inhibitory effects on Taxol-resistant oral cancer cells under hypoxia. Mol Med Rep 2015, 11, 2935-2940, doi:10.3892/mmr.2014.3080.
Dyrstad, S.E.; Lotsberg, M.L.; Tan, T.Z.; Pettersen, I.K.N.; Hjellbrekke, S.; Tusubira, D.; Engelsen, A.S.T.; Daubon, T.; Mourier, A.; Thiery, J.P., et al. Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells. Cancers (Basel) 2021, 13, doi:10.3390/cancers13050941.
Lucido, C.T.; Miskimins, W.K.; Vermeer, P.D. Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC. Cancers (Basel) 2018, 10, doi:10.3390/cancers10120476.
Bizjak, M.; Malavasic, P.; Dolinar, K.; Pohar, J.; Pirkmajer, S.; Pavlin, M. Combined treatment with Metformin and 2-deoxy glucose induces detachment of viable MDA-MB-231 breast cancer cells in vitro. Sci Rep 2017, 7, 1761, doi:10.1038/s41598-017-01801-5.
Tong, J.; Xie, G.; He, J.; Li, J.; Pan, F.; Liang, H. Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer. Journal of Biomedicine and Biotechnology 2011, 2011, 740564, doi:10.1155/2011/740564.
Stander, X.X.; Stander, B.A.; Joubert, A.M. Synergistic anticancer potential of dichloroacetate and estradiol analogue exerting their effect via ROS-JNK-Bcl-2-mediated signalling pathways. Cell Physiol Biochem 2015, 35, 1499-1526, doi:10.1159/000369710.
Hadzic, T.; Aykin-Burns, N.; Zhu, Y.; Coleman, M.C.; Leick, K.; Jacobson, G.M.; Spitz, D.R. Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic Biol Med 2010, 48, 1024-1033, doi:10.1016/j.freeradbiomed.2010.01.018.
Hardie, D.G. AMPK--sensing energy while talking to other signaling pathways. Cell Metab 2014, 20, 939-952, doi:10.1016/j.cmet.2014.09.013.
Srivastava, S.; Koay, E.J.; Borowsky, A.D.; De Marzo, A.M.; Ghosh, S.; Wagner, P.D.; Kramer, B.S. Cancer overdiagnosis: a biological challenge and clinical dilemma. Nat Rev Cancer 2019, 19, 349-358, doi:10.1038/s41568-019-0142-8.
Li, Z.; Sun, C.; Qin, Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics 2021, 11, 8322-8336, doi:10.7150/thno.62378.
Rosendahl Huber, A.; Pleguezuelos-Manzano, C.; Puschhof, J. A bacterial mutational footprint in colorectal cancer genomes. Br J Cancer 2021, 124, 1751-1753, doi:10.1038/s41416-021-01273-5.
Rodriguez, J.E.R.; Garcia-Perdomo, H.A. Role of monocarboxylate transporters in the diagnosis, progression, prognosis, and treatment of prostate cancer. Turk J Urol 2020, 46, 413-418, doi:10.5152/tud.2020.20278.
Ganapathy-Kanniappan, S.; Geschwind, J.F.; Kunjithapatham, R.; Buijs, M.; Syed, L.H.; Rao, P.P.; Ota, S.; Kwak, B.K.; Loffroy, R.; Vali, M. 3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines. Anticancer Res 2010, 30, 923-935.
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