Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells

详细信息    查看全文

• 作者：Julia Billiard (1)
  Jennifer B Dennison (4)
  Jacques Briand (2)
  Roland S Annan (2)
  Deping Chai (1)
  Mariela Colón (1)
  Christopher S Dodson (1)
  Seth A Gilbert (1)
  Joel Greshock (1)
  Junping Jing (1)
  Hong Lu (1)
  Jeanelle E McSurdy-Freed (1)
  Lisa A Orband-Miller (3)
  Gordon B Mills (4)
  Chad J Quinn (2)
  Jessica L Schneck (2)
  Gilbert F Scott (2)
  Anthony N Shaw (1)
  Gregory M Waitt (3)
  Richard F Wooster (1)
  Kevin J Duffy (1)
  
• 关键词：LDH ; Metabolism ; Aerobic glycolysis ; Cancer
• 刊名：Cancer & Metabolism
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：1
• 期：1
• 全文大小：530KB
• 参考文献：1. Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. / Science 2009, 324:1029-033. CrossRef
  2. Dang CV: MYC on the path to cancer. / Cell 2012, 149:22-5. CrossRef
  3. Giatromanolaki A, Sivridis E, Gatter KC, Turley H, Harris AL, Koukourakis MI: Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis. / Gynecol Oncol 2006, 103:912-18. CrossRef
  4. Kolev Y, Uetake H, Takagi Y, Sugihara K: Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. / Ann Surg Oncol 2008, 15:2336-344. CrossRef
  5. Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL: Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. / Br J Cancer 2003, 89:877-85. CrossRef
  6. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris 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, 24:4301-308. CrossRef
  7. 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, 9:425-34. CrossRef
  8. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. / Proc Natl Acad Sci USA 2010, 107:2037-042. CrossRef
  9. Qing G, Skuli N, Mayes PA, Pawel B, Martinez D, Maris JM, Simon MC: Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha. / Cancer Res 2010, 70:10351-0361. CrossRef
  10. Sheng SL, Liu JJ, Dai YH, Sun XG, Xiong XP, Huang G: Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. / FEBS J 2012, 279:3898-910. CrossRef
  11. Wang ZY, Loo TY, Shen JG, Wang N, Wang DM, Yang DP, Mo SL, Guan XY, Chen JP: LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis. / Breast Cancer Res Treat 2012, 131:791-00. CrossRef
  12. Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. / Mol Cancer Ther 2009, 8:626-35. CrossRef
  13. Yao F, Zhao T, Zhong C, Zhu J, Zhao H: LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. / Tumour Biol 2012, 34:25-1. CrossRef
  14. Yu Y, Deck JA, Hunsaker LA, Deck LM, Royer RE, Goldberg E, Vander Jagt DL: Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. / Biochem Pharmacol 2001, 62:81-9. CrossRef
  15. Minutolo F, Peters GJ, Sciarrillo R, Giovannetti E, Giannaccini G, Lucacchini A, Macchia M, Lanza M, Betti L, Tuccinardi T, Martinelli A, De Simone A, Salvetti I, Granchi C: N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation. / Eur J Med Chem 2011, 46:5398-407. CrossRef
  16. Granchi C, Roy S, Giacomelli C, Macchia M, Tuccinardi T, Martinelli A, Lanza M, Betti L, Giannaccini G, Lucacchini A, Funel N, Leon LG, Giovannetti E, Peters GJ, Palchaudhuri R, Calvaresi EC, Hergenrother PJ, Minutolo F: Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. / J Med Chem 2011, 54:1599-612. CrossRef
  17. Recanatini M, Sartini A, Giacomini E, Buonfiglio R, Roberti M, Di Stefano G, Manerba M, Vettraino M, Fiume L: Galloflavin (CAS 568-0-): a novel inhibitor of lactate dehydrogenase. / Chem Med Chem 2012, 7:311-17.
  18. Moorhouse AD, Spiteri C, Sharma P, Zloh M, Moses JE: Targeting glycolysis: a fragment based approach towards bifunctional inhibitors of hLDH-5. / Chem Commun (Camb) 2011, 47:230-32. CrossRef
  19. Farabegoli F, Vettraino M, Manerba M, Fiume L, Roberti M, Di Stefano G: Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. / Eur J Pharm Sci 2012, 47:729-38. CrossRef
  20. Greshock J, Bachman KE, Degenhardt YY, Jing J, Wen YH, Eastman S, McNeil E, Moy C, Wegrzyn R, Auger K, Hardwicke MA, Wooster R: Molecular target class is predictive of in vitro response profile. / Cancer Res 2010, 70:3677-686. CrossRef
  21. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. / Proc Natl Acad Sci USA 2005, 102:15545-5550. CrossRef
  22. Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E, Carver T, Asel E, Springer BA, Lane P, Salemme FR: High-density miniaturized thermal shift assays as a general strategy for drug discovery. / J Biomol Screen 2001, 6:429-40. CrossRef
  23. Hanke S, Besir H, Oesterhelt D, Mann M: Absolute SILAC for accurate quantitation of proteins in complex mixtures down to the attomole level. / J Proteome Res 2008, 7:1118-130. CrossRef
  24. McCleland ML, Adler AS, Shang Y, Hunsaker T, Truong T, Peterson D, Torres E, Li L, Haley B, Stephan JP, Belvin M, Hatzivassiliou G, Blackwood EM, Corson L, Evangelista M, Zha J, Firestein R: An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. / Cancer Res 2012, 72:5812-823. CrossRef
  25. Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Balko JM, Kuba MG, Sanders ME, Pinto JA, Gomez HL, Arteaga CL, Brown RE, Mills GB: Lactate Dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer. / Clin Cancer Res 2013, 19:3703-713. CrossRef
  26. Rogers GW, Brand MD, Petrosyan S, Ashok D, Elorza AA, Ferrick DA, Murphy AN: High throughput microplate respiratory measurements using minimal quantities of isolated mitochondria. / PLoS One 2011, 6:e21746. CrossRef
  27. Custodio JB, Cardoso CM, Madeira VM, Almeida LM: Mitochondrial permeability transition induced by the anticancer drug etoposide. / Toxicol In Vitro 2001, 15:265-70. CrossRef
  28. Ashizawa K, Willingham MC, Liang CM, Cheng SY: In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. / J Biol Chem 1991, 266:16842-6846.
  29. Hasmann M, Schemainda I: FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. / Cancer Res 2003, 63:7436-442.
  30. Davies B, Morris T: Physiological parameters in laboratory animals and humans. / Pharm Res 1993, 10:1093-095. CrossRef
  31. Ward RA, Brassington C, Breeze AL, Caputo A, Critchlow S, Davies G, Goodwin L, Hassall G, Greenwood R, Holdgate GA, Mrosek M, Norman RA, Pearson S, Tart J, Tucker JA, Vogtherr M, Whittaker D, Wingfield J, Winter J, Hudson K: Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation. / J Med Chem 2012, 55:3285-306. CrossRef
  32. Dalgarno DC, Zhu X, Shakespeare WC, Clackson T, Rivera V, Miret JJ, Xu Y, Xu R, Liu S, Kohlmann A, Zech SG, Li F, Zhou T, Squillace RM, Commodore L, Greenfield MT, Lu X, Miller DP, Huang WS, Qi J, Thomas RM, Wang Y, Zhang S, Dodd R: Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors. / J Med Chem 2013, 56:1023-040. CrossRef
  33. Zeiler M, Straube WL, Lundberg E, Uhlen M, Mann M: A Protein Epitope Signature Tag (PrEST) library allows SILAC-based absolute quantification and multiplexed determination of protein copy numbers in cell lines. / Mol Cell Proteomics 2012, 11:O111.
  34. Eszes CM, Sessions RB, Clarke AR, Moreton KM, Holbrook JJ: Removal of substrate inhibition in a lactate dehydrogenase from human muscle by a single residue change. / FEBS Lett 1996, 399:193-97. CrossRef
  35. Mazurek S: Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. / Int J Biochem Cell Biol 2011, 43:969-80. CrossRef
  36. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. / Nature 2008, 452:230-33. CrossRef
  37. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC: Evidence for an alternative glycolytic pathway in rapidly proliferating cells. / Science 2010, 329:1492-499. CrossRef
  38. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, / et al.: Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. / Nat Chem Biol 2012, 8:1008. CrossRef
  39. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. / Nat Cell Biol 2012, 14:1295-304. CrossRef
  
• 作者单位：Julia Billiard (1)
  Jennifer B Dennison (4)
  Jacques Briand (2)
  Roland S Annan (2)
  Deping Chai (1)
  Mariela Colón (1)
  Christopher S Dodson (1)
  Seth A Gilbert (1)
  Joel Greshock (1)
  Junping Jing (1)
  Hong Lu (1)
  Jeanelle E McSurdy-Freed (1)
  Lisa A Orband-Miller (3)
  Gordon B Mills (4)
  Chad J Quinn (2)
  Jessica L Schneck (2)
  Gilbert F Scott (2)
  Anthony N Shaw (1)
  Gregory M Waitt (3)
  Richard F Wooster (1)
  Kevin J Duffy (1)
  
  1. Cancer Metabolism DPU, GlaxoSmithKline, Collegeville, PA, USA
  4. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Platform Technology Sciences, GlaxoSmithKline, Collegeville, PA, USA
  3. Platform Technology Sciences, GlaxoSmithKline, Research Triangle Park, Chapel Hill, NC, USA
  
• ISSN：2049-3002

文摘

Background Most normal cells in the presence of oxygen utilize glucose for mitochondrial oxidative phosphorylation. In contrast, many cancer cells rapidly convert glucose to lactate in the cytosol, a process termed aerobic glycolysis. This glycolytic phenotype is enabled by lactate dehydrogenase (LDH), which catalyzes the inter-conversion of pyruvate and lactate. The purpose of this study was to identify and characterize potent and selective inhibitors of LDHA. Methods High throughput screening and lead optimization were used to generate inhibitors of LDHA enzymatic activity. Effects of these inhibitors on metabolism were evaluated using cell-based lactate production, oxygen consumption, and 13C NMR spectroscopy assays. Changes in comprehensive metabolic profile, cell proliferation, and apoptosis were assessed upon compound treatment. Results 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid was identified as an NADH-competitive LDHA inhibitor. Lead optimization yielded molecules with LDHA inhibitory potencies as low as 2 nM and 10 to 80-fold selectivity over LDHB. Molecules in this family rapidly and profoundly inhibited lactate production rates in multiple cancer cell lines including hepatocellular and breast carcinomas. Consistent with selective inhibition of LDHA, the most sensitive breast cancer cell lines to lactate inhibition in hypoxic conditions were cells with low expression of LDHB. Our inhibitors increased rates of oxygen consumption in hepatocellular carcinoma cells at doses up to 3 microM, while higher concentrations directly inhibited mitochondrial function. Analysis of more than 500 metabolites upon LDHA inhibition in Snu398 cells revealed that intracellular concentrations of glycolysis and citric acid cycle intermediates were increased, consistent with enhanced Krebs cycle activity and blockage of cytosolic glycolysis. Treatment with these compounds also potentiated PKM2 activity and promoted apoptosis in Snu398 cells. Conclusions Rapid chemical inhibition of LDHA by these quinoline 3-sulfonamids led to profound metabolic alterations and impaired cell survival in carcinoma cells making it a compelling strategy for treating solid tumors that rely on aerobic glycolysis for survival.