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  • 1 Szent Lázár Megyei Kórház, Salgótarján, Füleki út 54–56., 3100
  • 2 Semmelweis Egyetem, Általános Orvostudomániy Kar, Budapest
Open access

Absztrakt:

A rosszindulatú daganatsejtek többségében fokozott a glikolízis, amely biztosítja a proliferációhoz szükséges energia legnagyobb részét. A laktátdehidrogenáz (LDH) anaerob körülmények között katalizálja a reverzibilis piruvát–tejsav átalakulást. A daganatsejtek által expresszált LDHA izoenzim hatására a tejsavképződés jelentősen fokozódik. A tejsav indukálja az oxigenizált daganatsejtek proliferációját, az angiogenezist és gátolja a veleszületett és az adaptív immunválaszt. A szérum-LDH-emelkedés rövidebb túléléssel korrelál. A szerzők áttekintik az LDH-emelkedés és a rosszindulatú daganatos betegségek prognózisa közötti összefüggést feltáró fontosabb vizsgálatokat. Orv Hetil. 2017; 158(50): 1977–1988.

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  • 1

    Miao P, Sheng S, Sun X, et al. Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life 2013; 65: 904–910.

  • 2

    El Mjiyad N, Caro-Maldonado A, Ramirez-Peinado S, et al. Sugar-free approaches to cancer cell killing. Oncogene 2011; 30: 253–264.

  • 3

    Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006; 9: 425–434.

  • 4

    Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H, et al. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016; 7: 52.

  • 5

    Brown JE, Cook RJ, Lipton A, et al. Serum lactate dehydrogenase is prognostic for survival in patients with bone metastases from breast cancer: a retrospective analysis in bisphosphonate-treated patients. Clin Cancer Res. 2012; 18: 6348–6355.

  • 6

    Le A, Cooper CR, Gouw AM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 2010; 107: 2037–2042.

  • 7

    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85–95.

  • 8

    Semenza GL. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life 2008; 60: 591–597.

  • 9

    Wokolorczyk D, Gliniewicz B, Sikorski A, et al. A range of cancers is associated with the rs6983267 marker on chromosome 8. Cancer Res. 2008; 68: 9982–9986.

  • 10

    Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway – a report of the Tumour Angiogenesis Research Group. J Clin Oncol. 2006; 24: 4301–4308.

  • 11

    Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.

  • 12

    Zhao YH, Zhou M, Liu H, et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 2009; 28: 3689–3701.

  • 13

    Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011; 145: 732–744.

  • 14

    Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2011; 2: 551–556.

  • 15

    Yang W, Zheng Y, Xia Y, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012; 14: 1295–1304.

  • 16

    Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013; 17: 113–124.

  • 17

    Xie H, Valera VA, Merino MJ, et al. LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 2009; 8: 626–635.

  • 18

    Ashrafian H, O’Flaherty L, Adam J, et al. Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res. 2010; 70: 9153–9165.

  • 19

    Mantovani A. Macrophages, neutrophils, and cancer: a double edged sword. New J Sci. 2014; 2014: Article ID 271940.

  • 20

    Tran Janco JM, Lamichhane P, Karyampudi L, et al. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 2015; 194: 2985–2991.

  • 21

    Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015; 25: 771–784.

  • 22

    Newsholme P, Gordon S, Newsholme EA. Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Biochem J. 1987; 242: 631–636.

  • 23

    Galvan-Pena S, O’Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol. 2014, 5: 420.

  • 24

    Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008; 18: 349–355.

  • 25

    Pearce EJ, Everts B. Dendritic cell metabolism. Nat Rev Immunol. 2015; 15: 18–29.

  • 26

    Krawczyk CM, Holowka T, Sun J, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115: 4742–4749.

  • 27

    Jantsch J, Chakravortty D, Turza N, et al. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol. 2008; 180: 4697–4705.

  • 28

    Everts B, Amiel E, Huang SC, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014; 15: 323–332.

  • 29

    Frauwirth KA, Riley JL, Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16: 769–777.

  • 30

    Jacobs SR, Herman CE, Maciver NJ, et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol. 2008; 180: 4476–4486.

  • 31

    Caro-Maldonado A, Wang R, Nichols AG, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014; 192: 3626–3636.

  • 32

    Halestrap AP, Denton RM. Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by alpha-cyano-4-hydroxycin-namate. Biochem J. 1974; 138: 313–316.

  • 33

    Palmieri F, Bisaccia F, Capobianco L, et al. Mitochondrial metabolite transporters. Biochim Biophys Acta 1996; 1275: 127–132.

  • 34

    Price NT, Jackson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J. 1998; 329(Pt 2): 321–328.

  • 35

    Cheeti S, Warrier BK, Lee CH. The role of monocarboxylate transporters in uptake of lactic acid in HeLa cells. Int J Pharm. 2006; 325: 48–54.

  • 36

    Halestrap AP. The monocarboxylate transporter family – structure and functional characterization. IUBMB Life 2012; 64: 1–9.

  • 37

    Tan Z, Xie N, Banerjee S, et al. The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages. J Biol Chem. 2015; 290: 46–55.

  • 38

    Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol. 2009; 92: 329–333.

  • 39

    Sonveaux P, Vegran F, Schroeder T, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008; 118: 3930–3942.

  • 40

    Curry JM, Tuluc M, Whitaker-Menezes D, et al. Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 2013; 12: 1371–1384.

  • 41

    Lamb R, Harrison H, Hulit J, et al. Mitochondria as new therapeutic targets for eradicating cancer stem cells: quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget 2014; 5: 11029–11037.

  • 42

    Romero-Garcia S, Lopez-Gonzalez JS, Baez-Viveros JL, et al. Tumor cell metabolism: an integral view. Cancer Biol Ther. 2011; 12: 939–948.

  • 43

    Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013; 123: 3685–3692.

  • 44

    Fang J, Quinones QJ, Holman TL, et al. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol. 2006; 70: 2108–2115.

  • 45

    Pinheiro C, Longatto-Filho A, Scapulatempo C, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008; 452: 139–146.

  • 46

    De Oliveira AT, Pinheiro C, Longatto-Filho A, et al. Co-expression of monocarboxylate transporter 1 (MCT1) and its chaperone (CD147) is associated with low survival in patients with gastrointestinal stromal tumors (GISTs). J Bioenerg Biomembr. 2012; 44: 171–178.

  • 47

    Xie H, Hanai J, Re JG, et al. Targeting lactate dehydrogenase – an inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 2014; 19: 795–809.

  • 48

    Fischer K, Hoffmann P, Voelkl S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007; 109: 3812–3819.

  • 49

    Calcinotto A, Filipazzi P, Grioni M, et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012; 72: 2746–2756.

  • 50

    Choi SY, Collins CC, Gout PW, et al. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol. 2013; 230: 350–355.

  • 51

    Singer K, Kastenberger M, Gottfried E, et al. Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8+ T-cell infiltration in the tumor. Int J Cancer 2011; 128: 2085–2095.

  • 52

    Feder-Mengus C, Ghosh S, Weber W, et al. Multiple mechanisms underlie defective recognition of melanoma cells cultured in three-dimensional architectures by antigen-specific cytotoxic T lymphocytes. Br J Cancer 2007; 96: 1072–1082.

  • 53

    Mendler AN, Hu B, Prinz PU, et al. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 2012; 131: 633–640.

  • 54

    Kato Y, Ozawa S, Tsukuda M, et al. Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanoma. FEBS J. 2007; 274: 3171–3183.

  • 55

    Fukumura D, Xu L, Chen Y, et al. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 2001; 61: 6020–6024.

  • 56

    Xu L, Fukumura D, Jain RK. Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. J Biol Chem. 2002; 277: 11368–11374.

  • 57

    Shi Q, Abbruzzese JL, Huang S, et al. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res. 1999; 5: 3711–3721.

  • 58

    Shi Q, Le X, Wang B, et al. Regulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cells. J Interferon Cytokine Res. 2000; 20: 1023–1028.

  • 59

    Xu L, Fidler IJ. Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res. 2000; 60: 4610–4616.

  • 60

    Hunt TK, Aslam RS, Beckert S, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007; 9: 1115–1124.

  • 61

    Porporato PE, Payen VL, De Saedeleer CJ, et al. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 2012; 15: 581–592.

  • 62

    Vegran F, Boidot R, Michiels C, et al. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011; 71: 2550–2560.

  • 63

    Pavlides S, Whitaker-Menezes D, Castello-Cros R, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8: 3984–4001.

  • 64

    Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513: 559–563.

  • 65

    Ohashi T, Akazawa T, Aoki M, et al. Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity. Int J Cancer 2013; 133: 1107–1118.

  • 66

    Crane CA, Austgen K, Haberthur K, et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci USA 2014; 111: 12823–12828.

  • 67

    Peter K, Rehli M, Singer K, et al. Lactic acid delays the inflammatory response of human monocytes. Biochem Biophys Res Commun. 2015; 457: 412–418.

  • 68

    Gottfried E, Kunz-Schughart LA, Ebner S, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 2006; 107: 2013–2021.

  • 69

    Nasi A, Fekete T, Krishnamurthy A, et al. Dendritic cell reprogramming by endogenously produced lactic acid. J Immunol. 2013; 191: 3090–3099.

  • 70

    Dong H, Bullock TN. Metabolic influences that regulate dendritic cell function in tumors. Front Immunol. 2014; 5: 24.

  • 71

    Husain Z, Seth P, Sukhatme VP. Tumor-derived lactate and myeloid-derived suppressor cells: linking metabolism to cancer immunology. Oncoimmunology 2013; 2: e26383.

  • 72

    Husain Z, Huang Y, Seth P, et al. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013; 191: 1486–1495.

  • 73

    Shime H, Yabu M, Akazawa T, et al. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol. 2008; 180: 7175–7183.

  • 74

    Nagae M, Hiraga T, Yoneda T. Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization. J Bone Miner Metab. 2007; 25: 99–104.

  • 75

    Lee DK, Nguyen T, Lynch KR, et al. Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 2001; 275: 83–91.

  • 76

    Cai TQ, Ren N, Jin L, et al. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun. 2008; 377: 987–991.

  • 77

    Mosienko V, Teschemacher AG, Kasparov S. Is L-lactate a novel signaling molecule in the brain? J Cereb Blood Flow Metab. 2015; 35: 1069–1075.

  • 78

    Liu C, Kuei C, Zhu J, et al. 3,5-dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. J Pharmacol Exp Ther. 2012; 341: 794–801.

  • 79

    Lauritzen KH, Morland C, Puchades M, et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 2014; 24: 2784–2795.

  • 80

    Liu C, Wu J, Zhu J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem. 2009; 284: 2811–2822.

  • 81

    Roland CL, Arumugam T, Deng D, et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res. 2014; 74: 5301–5310.

  • 82

    Yang J, Ruchti E, Petit JM, et al. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci USA 2014; 111: 12228–12233.

  • 83

    Rong Y, Wu W, Ni X, et al. Lactate dehydrogenase A is overexpressed in pancreatic cancer and promotes the growth of pancreatic cancer cells. Tumour Biol. 2013; 34: 1523–1530.

  • 84

    Yao F, Zhao T, Zhong C, et al. LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol. 2013; 34: 25–31.

  • 85

    Lim KS, Lim KJ, Price AC, et al. Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner. Oncogene 2014; 33: 4433–4441.

  • 86

    Morais-Santos F, Granja S, Miranda-Gonçalves V, et al. Targeting lactate transport suppresses in vivo breast tumour growth. Oncotarget 2015; 6: 19177–19189.

  • 87

    Gallagher SM, Castorino JJ, Wang D, et al. Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 2007; 67: 4182–4189.

  • 88

    Izumi H, Takahashi M, Uramoto H, et al. Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci. 2011; 102: 1007–1013.

  • 89

    Mathupala SP, Parajuli P, Sloan AE. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 2004; 55: 1410–1419.

  • 90

    Colen CB, Seraji-Bozorgzad N, Marples B, et al. Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study. Neurosurgery 2006; 59: 1313–1323.

  • 91

    Miranda-Goncalves V, Honavar M, Pinheiro C, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 2013; 15: 172–188.

  • 92

    Polanski R, Hodgkinson CL, Fusi A, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014; 20: 926–937.

  • 93

    Colgan SM, Mukherjee S, Major P. Hypoxia-induced lactate dehydrogenase expression and tumor angiogenesis. Clin Colorectal Cancer 2007; 6: 442–446.

  • 94

    Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy. Clin Cancer Res. 2011; 17: 4892–4900.

  • 95

    Suh SY, Ahn HY. Lactate dehydrogenase as a prognostic factor for survival time of terminally ill cancer patients: a preliminary study. Eur J Cancer 2007; 43: 1051–1059.

  • 96

    Walenta S, Wetterling M, Lehrke M, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000; 60: 916–921.

  • 97

    Saraswathy S, Crawford FW, Lamborn KR, et al. Evaluation of MR markers that predict survival in patients with newly diagnosed GBM prior to adjuvant therapy. J Neurooncol. 2009; 91: 69–81.

  • 98

    Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol. 2004; 14: 267–274.

  • 99

    Ziebart T, Walenta S, Kunkel M, et al. Metabolic and proteomic differentials in head and neck squamous cell carcinomas and normal gingival tissue. J Cancer Res Clin Oncol. 2011; 137: 193–199.

  • 100

    Wulaningsih W, Holmberg L, Garmo H, et al. Serum lactate dehydrogenase and survival following cancer diagnosis. Br J Cancer 2015; 113: 1389–1396.

  • 101

    Liu R, Cao J, Gao X. Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L. Tumor Biol. 2016; 37: 14083–14088.

  • 102

    Hermes A, Gatzemeier U, Waschki B, et al. Lactate dehydrogenase as prognostic factor in limited and extensive disease stage small cell lung cancer – A retrospective single institution analysis. Resp Med. 2010; 104: 1937–1942.

  • 103

    Chen B, Dai D, Tang H, et al. Pre-treatment serum alkaline phosphatase and lactate dehydrogenase as prognostic factors in triple negative breast cancer. J Cancer 2016; 7: 2309–2316.

  • 104

    Liu X, Meng QH, Ye Y, et al. Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. Carcinogenesis 2015; 36: 243–248.

  • 105

    Ji F, Fu SJ, Guo ZY, et al. Prognostic value of combined preoperative lactate dehydrogenase and alkaline phosphatase levels in patients with resectable pancreatic ductal adenocarcinoma. Medicine (Baltimore) 2016; 95: e4065.

  • 106

    Li J, Wu MF, Lu, HW, et al. Pretreatment serum lactate dehydrogenase is an independent prognostic factor for patients receiving neoadjuvant chemotherapy for locally advanced cervical cancer. Cancer Med. 2016; 5: 1863–1872.

  • 107

    Verma A, Phua CK, Sim WY, et al. Pleural LDH as a prognostic marker in adenocarcinoma lung with malignant pleural effusion. Medicine (Baltimore) 2016; 95: e3996.

  • 108

    Petrelli F, Cabiddu M, Coinu A, et al. Prognostic role of lactate dehydrogenase in solid tumors: a systematic review and meta-analysis of 76 studies. Acta Oncol. 2015; 54: 961–970.

  • 109

    Zhang J, Yao YH, Li BG, et al. Prognostic value of pretreatment serum lactate dehydrogenase level in patients with solid tumors: a systematic review and meta-analysis. Sci Rep. 2015; 5: 9800.

  • 110

    Shen J, Chen Z, Zhuang Q, et al. Prognostic value of serum lactate dehydrogenase in renal cell carcinoma: A systematic review and meta-analysis. PLoS One 2016; 11: e0166482.

  • 111

    Li G, Wang Z, Xu J, et al. The prognostic value of lactate dehydrogenase levels in colorectal cancer: a meta-analysis. BMC Cancer 2016; 16: 249.

  • 112

    Lis P, Dyląg M, Niedźwiecka K, et al. The HK2 dependent “warburg effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules 2016; 21: pii: E1730.

  • 113

    El Sayed SM, Mohamed WG, Seddik MA, et al. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chinese J Cancer 2014; 33: 356–364.

  • 114

    Stein MN, Hussain M, Stadler WM, et al. A phase II study of AT-101 to overcome Bcl-2 – mediated resistance to androgen deprivation therapy in patients with newly diagnosed castration-sensitive metastatic prostate cancer. Clin Genitourin Cancer 2016; 14: 22–27.

  • 115

    Swiecicki PL, Bellile E, Sacco AG, et al. A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drugs 2016; 34: 481–489.