A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness

European Journal of Medicinal Chemistry

Volumn 87, Issue , 2014, Pages 745-758

  Barcelos, Rosimeire Coura ^a   Pelizzaro Rocha, Karin Juliane ^a   Pastre, Julio Cezar ^a   Dias, Marina Pereira ^a   Ferreira Halder, Carmen Veríssima ^a   Pilli, Ronaldo Aloise ^a  

^a UNIVERSITY OF CAMPINAS   (Brazil)

Author keywords

AXL kinase; Goniothalamin; HIF 1 ; N acylated aza derivatives; Panc 1 cells; Pancreatic cancer

Indexed keywords

1 ACETYL 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 ACRYLOYL 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 BUT 2 ENOYL 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 CINNAMOYL 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 (3,4 DIHYDROXY 3 METHOXYPHENYL)ACRYLOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 (3,4 DIHYDROXYPHENYL)ACRYLOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 (3,4 DIHYDROXYPHENYL)PROPANOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 [3,4 BIS(TERT BUTYLDIMETHYLSILYLOXY) 3 METHOXYPHENYL]ACRYLOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 [3,4 BIS(TERT BUTYLDIMETHYLSILYLOXY)PHENYL]ACRYLOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 1 [3 [3,4 BIS(TERT BUTYLDIMETHYLSILYLOXY)PHENYL]PROPANOYL] 6 STYRYL 5,6 DIHYDROPYRIDIN 2(1H) ONE; 6 STYRYL 1 [3 (3,4,5 TRIMETHOXYPHENYL)ACRYLOYL] 5,6 DIHYDROPYRIDIN 2(1H) ONE; ANTINEOPLASTIC AGENT; CASPASE 3; CYCLIN D1; GLUTATHIONE; GONIOTHALAMIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; LACTONE DERIVATIVE; METHYL 2 OXO 6 STYRYL 5,6 DIHYDROPYRIDINE 1(2H) CARBOXYLATE; MITOGEN ACTIVATED PROTEIN KINASE 1; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE AXL; REACTIVE OXYGEN METABOLITE; UNCLASSIFIED DRUG; VASCULOTROPIN;

ACYLATION; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; CELL CYCLE ARREST; CELL DEATH; CELL PROLIFERATION; CELL VIABILITY; COLONY FORMATION; CYTOTOXICITY; DOWN REGULATION; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ELECTROPHILICITY; ENZYME ACTIVATION; HUMAN; HUMAN CELL; IC50; KERATINOCYTE; MTT ASSAY; NUCLEOPHILICITY; ONCOGENE C MYC; OXIDATION REDUCTION STATE; PANCREAS CANCER; PANCREATIC CANCER CELL LINE; PROTON NUCLEAR MAGNETIC RESONANCE; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; WESTERN BLOTTING;

EID: 84949115049     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2014.09.085     Document Type: Article

References (82)

1. R. Siegel, D.M.A. Naishadham, A. Jemal, Cancer statistics, 2014, CA Cancer J. Clin. 64 (2014) 9-29.
2. C.J. Yeo, J.L. Cameron, K.D. Lillemoe, T.A. Sohn, K.A. Campbell, P.K. Sauter, J. Coleman, R.A. Abrams, R.H. Hruban, Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality, Ann. Surg. 236 (2002) 355-366.
3. A. Maitra, R.H. Hruban, Pancreatic cancer, Annu. Rev. Pathol. 3 (2008) 157-188.
4. E.J. Kim, D.M. Simeone, Advances in pancreatic cancer, Curr. Opin. Gastroen. 27 (2011) 460-466.
5. J.B.M. Koorstra, C.A. Karikari, S.B. Feldmann, P.L. Rojas, G.J.A. Offerhaus, H. Alvarez, A. Maitra, The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target, Cancer Biol. Ther. 8 (2009) 618-626;
6. (b) C. Gjerdrum, C. Tiron, T. Høiby, I. Stefansson, H. Haugen, T. Sandal, K. Collett, S. Li, E. McCormack, B.T. Gjertsen, D.R. Micklem, L.A. Akslen, C. Glackin, J.B. Lorens, Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 1124-1129;
7. (c) X. Ye, Y. Li, S. Stawicki, S. Couto, J. Eastham-Anderson, D. Kallop, R. Weimer, Y.L. Wu, An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies, Oncogene 29 (2010) 5254-5264;
8. (d) E.B. Rankin, K.C. Fuh, T.E. Taylor, A.J. Krieg, M. Musser, J. Yuan, K. Wei, C.J. Kuo, T.A. Longacre, A.J. Giaccia, AXL is an essential factor and therapeutic target for metastatic ovarian cancer, Cancer Res. 70 (2010) 7570-7579.
9. A. Verma, S.L. Warner, H. Vankayalapati, D.J. Bearss, S. Sharma, Targeting Axl and Mer kinases in cancer, Mol. Cancer Ther. 10 (2011) 1763-1773.
10. J.M. Brown, Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies, Mol. Med. Today 6 (2000) 157-162.
11. H.C. Sun, Z.J. Qiu, J. Liu, J. Sun, T. Jiang, K.J. Huang, M. Yao, C. Huang, Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis, Int. J. Oncol. 30 (2007) 1359-1367;
12. (b) G.L. Semenza, Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics, Oncogene 29 (2010) 625-634.
13. A.C. Koong, V.K. Mehta, Q.T. Le, G.A. Fisher, D.J. Terris, J.M. Brown, A.J. Bastidas, M. Vierra, Pancreatic tumors show high levels of hypoxia, Int. J. Radiat. Oncol. Biol. Phys. 48 (2000) 919-922.
14. D.J. Newman, G.M. Cragg, Natural products as sources of new drugs over the 30 years from 1981 to 2010, J. Nat. Prod. 75 (2012) 311-335.
15. A. de Fatima, L.V. Modolo, L.S. Conegero, R.A. Pilli, C.V. Ferreira, L.K. Kohn, J.E. de Carvalho, Styryl lactones and their derivatives: biological activities, mechanisms of action and potential leads for drug design, Curr. Med. Chem. 13 (2006) 3371-3384.
16. A. de Fatima, L.K. Kohn, M.A. Ant^onio, J.E. de Carvalho, R.A. Pilli, (R)-Goniothalamin: total synthesis and cytotoxic activity against cancer cell lines, Bioorg. Med. Chem. 13 (2005) 2927-2933;
17. (b) A. de F-atima, L.K. Kohn, J.E. Carvalho, R.A. Pilli, Cytotoxic activity of (S)-goniothalamin and analogues against human cancer cells, Bioorg. Med. Chem. 14 (2006) 622-6531;
18. (c) C.C. Chiu, P.L. Liu, K.J. Huang, H.M. Wang, K.F. Chang, C.K. Chou, F.R. Chang, I.W. Chong, K. Fang, J.S. Chen, H.W. Chang, Y.C. Wu, Goniothalamin inhibits growth of human lung cancer cells through DNA damage, apoptosis, and reduced migration ability, J. Agric. Food Chem. 59 (2011) 4288-4293;
19. (d) M. Al-Qubaisi, R. Rozita, S.-K. Yeap, A.-R. Omar, A.-M. Ali, N.B. Alitheen, Selective cytotoxicity of goniothalamin against hepatoblastoma Hepg2 cells, Molecules 16 (2011) 2944-2959;
20. (e) D.B. Vendramini-Costa, I.B. de Castro, A.L. Ruiz, C. Marquissolo, R.A. Pilli, J.E. de Carvalho, Effect of goniothalamin on the development of Ehrlich solid tumor in mice, Bioorg. Med. Chem. 18 (2010) 6742-6747.
21. S.H. Inayat-Hussain, B.O. Annuar, L.B. Din, A.M. Ali, D. Ross, Loss of mitochondrial transmembrane potential and caspase-9 activation during apoptosis induced by the novel styryl-lactone goniothalamin in HL-60 leukemia cells, Toxicol. Vitro 17 (2003) 433-439;
22. (b) S.H. Inayat-Hussain, A.B. Osman, L.B. Din, A.M. Ali, R.T. Snowden, M. MacFarlane, K. Cain, Caspases-3 and-7 are activated in goniothalamininduced apoptosis in human Jurkat T-cells, FEBS Lett. 456 (1999) 379-383;
23. (c) A. de Fatima, W.F. Zambuzzi, L.V. Modolo, C.A.B. Tarsitano, F.R. Gadelha, S. Hylsop, J.E. de Carvalho, I. Salgado, C.V. Ferreira, R.A. Pilli, Cytotoxicity of goniothalamin enantiomers in renal cancer cells: involvement of nitric oxide, apoptosis and autophagy, Chem. Biol. Interact. 176 (2008) 143-150;
24. (d) J.-Y. Wach, S. Güttinger, U. Kutay, K. Gademann, The cytotoxic styryl lactone goniothalamin is an inhibitor of nucleocytoplasmic transport, Bioorg. Med. Chem. Lett. 20 (2010) 2843-2846;
25. (e) F.S. Zhou, W.D. Tang, Q. Mu, G.X. Yang, Y. Wang, G.L. Liang, L.G. Lou, Semisynthesis and antitumor activities of new styryl-lactone derivatives, Chem. Pharm. Bull. 11 (2005) 1387-1391;
26. (f) P. Kasaplar, O. Yilmazer, A. Cą-gir, 6-Bicycloaryl substituted (S)-and (R)-5,6-dihydro-2H-pyran-2-ones: asymmetric synthesis and antiproliferative properties, Bioorg. Med. Chem. 17 (2009) 311-318;
27. (g) R.C. Barcelos, J.C. Pastre, V. Caixeta, D. Vendramini-Costa, J.E. de Carvalho, R.A. Pilli, Synthesis of methoxylated goniothalamin, aza-goniothalamin and gpyrones and their in vitro evaluation against human cancer cells, Bioorg. Med. Chem. 20 (2012) 3635-3651;
28. (h) M. Bruder, D.B. Vendramini-Costa, J.E. De Carvalho, R.A. Pilli, Design, synthesis and in vitro evaluation against human cancer cells of 5-methyl-5-styryl-2,5-dihydrofuran-2-ones, a new series of goniothalamin analogues, Bioorg. Med. Chem. 21 (2013) 5107-5117.
29. L. Bialy, H. Waldmann, Synthesis and biological evaluation of cytostatin analogues, Chem. Commun. 7 (2003) 1872-1873;
30. (b) S.B. Buck, C. Hardouin, S. Ichikawa, D.R. Soenen, C.-M. Gauss, I. Hwang, M.R. Swingle, K.M. Bonness, R.E. Honkanen, D.L. Boger, Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition, J. Am. Chem. Soc. 125 (2003) 15694-15695.
31. J. Mulzer, K. Altmann, G. Hofle, R. Müller, K.C.R. Prantz, Epothilones e a fascinating family of microtubule stabilizing antitumor agents, C. R. Chim. 11 (2008) 1336-1368;
32. (b) http://www.cancer.gov/cancertopics/druginfo/fda-ixabepilone (accessed 16.04.14.).
33. L. Raj, T. Ide, A.U. Gurkar, M. Foley, M. Schenone, X. Li, N.J. Tolliday, T.R. Golub, S.A. Carr, A.F. Shamji, A.M. Stern, A. Mandinova, S.L. Schreiber, S.W. Lee, Selective killing of cancer cells by a small molecule targeting the stress response to ROS, Nature 475 (2011) 231-234;
34. (b) D.J. Adams, M. Dai, G. Pellegrino, B.K. Wagner, A.M. Stern, A.F. Shamji, S.L. Schreiber, Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 15115-15120;
35. (c) D.P. Bezerra, C. Pessoa, M.O. De Moraes, N. Saker-Neto, E.R. Silveira, L.V. Costa-Lotufo, Overview of the therapeutic potential of piplartine (piperlongumine), Eur. J. Pharm. Sci. 48 (2013) 453-463.
36. B. Sipos, S. Moser, H. Kalthoff, V. Torok, M. Lohr, G. Kloppel, A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform, Virchows Arch. 442 (2003) 444-452.
37. M. Hagel, D. Niu, T. St Martin, M.P. Sheets, L. Qiao, H. Bernard, R.M. Karp, Z. Zhu, M.T. Labenski, P. Chaturvedi, M. Nacht, W.F. Westlin, R.C. Petter, J. Singh, Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine, Nat. Chem. Biol. 7 (2011) 22-24.
38. I.M. Serafimova, M.A. Pufall, S. Krishnan, K. Duda, M.S. Cohen, R.L. Maglathlin, J.M. McFarland, R.M. Miller, M. Frodin, J. Taunton, Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles, Nat. Chem. Biol. 8 (2012) 471-476.
39. C.A. Gomes, T.G. Da Cruz, J.L. Andrade, N. Milhazes, F. Borges, M.P.M. Marques, Anticancer activity of phenolic acids of natural or synthetic origin: a structureeactivity study, J. Med. Chem. 46 (2003) 5395-5401;
40. (b) T.-W. Chung, S.-K. Moon, Y.-C. Chang, J.-H. Ko, Y.-C. Lee, G. Cho, S.-H. Kim, J.-G. Kim, C.-H. Kim, Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism, FASEB J. 18 (2004) 1670-1681.
41. T. Nakagawa, M. Shimizu, Y. Shirakami, H. Tatebe, I. Yasuda, H. Tsurumi, H. Moriwaki, Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells, Cancer Lett. 273 (2009) 250-256;
42. (b) P.A. Phillips, V. Sangwan, D. Borja-Cacho, V. Dudeja, S.M. Vickers, A.K. Saluja, Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, Cancer Lett. 308 (2011) 181-188;
43. (c) S.K. Roy, Q. Chen, J. Fu, S. Shankar, R.K. Srivastava, Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors, PLoS One 6 (2011) e25166;
44. (d) W. Wang, L. Ao, E.R. Rayburn, H. Xu, X. Zhang, X. Zhang, S.A. Nag, X. Wu, M.-H. Wang, H. Wang, E.G. Van Meir, R. Zhang, KCN1, a novel synthetic sulfonamide anticancer agent: in vitro and in vivo anti-pancreatic cancer activities and preclinical pharmacology, PLoS One 7 (2012) e44883;
45. (e) K.J. Pelizzaro-Rocha, M.B. de Jesus, R.R. Ruela-de-Sousa, C.V. Nakamura, F.S. Reis, A. de F-atima, C.V. Ferreira-Halder, Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy, Biochim. Biophys. Acta 1833 (2013) 2856-2865.
46. G.K. Balendiran, R. Dabur, D. Fraser, The role of glutathione in cancer, Cell Biochem. Funct. 22 (2004) 343-352.
47. T.J. Schmidt, Helenanolide-type sesquiterpene lactoneseIII. Rates and stereochemistry in the reaction of helenalin and related helenanolides with sulfhydryl containing biomolecules, Bioorg. Med. Chem. 5 (1997) 645-653;
48. (b) T.J. Schmidt, G. Lyb, H.L. Pahl, I. Merfort, Helenanolide type sesquiterpene lactones. Part 5: the role of glutathione addition under physiological conditions, Bioorg. Med. Chem. 7 (1999) 2849-2855;
49. (c) J. Heilmann, M.R. Wasescha, T.J. Schmidt, The influence of glutathione and cysteine levels on the cytotoxicity of helenanolide type sesquiterpene lactones against KB cells, Bioorg. Med. Chem. 9 (2001) 2189-2194;
50. (d) P.A. Whitton, A. Lau, A. Salisbury, J. Whitehouse, C.S. Evans, Kava lactones and the kava-kava controversy, Phytochemistry 64 (2003) 673-679;
51. (e) E. Butturini, E. Cavalieri, A.C. De Prati, E. Darra, A. Rigo, K. Shoji, N. Murayama, H. Yamazaki, Y. Watanabe, H. Suzuki, S. Mariotto, Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation, PLoS One 6 (2011) e20174.
52. A.E. Mitchell, J. Zheng, B.D. Hammock, M. Lo Bello, A.D. Jones, Structural and functional consequences of haloenol lactone inactivation of murine and human glutathione S-transferase, Biochemistry 37 (1998) 6752-6759;
53. (b) J. Zheng, A.E. Mitchell, A.D. Jones, B.D. Hammock, Haloenol lactone is a new isozyme-selective and active site-directed inactivator of glutathione S-transferase, J. Biol. Chem. 271 (1996) 20421-20425.
54. S. Gansauge, F. Gansauge, M. Ramadani, H. Stobbe, B. Rau, N. Harada, H.G. Beger, Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis, Cancer Res. 57 (1997) 1634-1637.
55. R.A. Weinberg, The retinoblastoma protein and cell cycle control, Cell 81 (1995) 323-330.
56. A. Skoudy, I. Hernandez-Mu~noz, P. Navarro, Pancreatic ductal adenocarcinoma and transcription factors: role of c-Myc, J. Gastrointest. Cancer 42 (2011) 76-84.
57. D.J. Liao, A. Thakur, J. Wu, H. Biliran, F.H. Sarkar, Perspectives on c-Myc, cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy, Crit. Rev. Oncog. 13 (2007) 93-158.
58. L. Liu, J. Greger, H. Shi, Y. Liu, J. Greshock, R. Annan, W. Halsey, G.M. Sathe, A.M. Martin, T.M. Gilmer, Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL, Cancer Res. 69 (2009) 6871-6878;
59. (b) W. Qi, L.S. Cooke, A. Stejskal, C. Riley, K.D. Croce, J.W. Saldanha, D. Bearss, D. Mahadevan, MP470, a novel receptor tyrosine kinase inhibitor, in combination with erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer, BMC Cancer 9 (2009) 142-154.
60. K. Balmanno, S.J. Cook, Tumour cell survival signalling by the ERK1/2 pathway, Cell. Death Differ. 16 (2009) 368-377.
61. A. Shih, F.B. Davis, H.Y. Lin, P.J. Davis, Resveratrol induces apoptosis in thyroid cancer cell lines via a MAPK-and p53-dependent mechanism, J. Clin. Endocrinol. Metab. 87 (2002) 1223-1232.
62. Y.H. Kim, D.H. Lee, J.H. Jeong, Z.S. Guo, Y.J. Lee, Quercetin augments TRAILinduced apoptotic death: involvement of the ERK signal transduction pathway, Biochem. Pharmacol. 75 (2008) 1946-1958.
63. F. Llorens, F.A. Miro, A. Casanas, N. Roher, L. Garcia, M. Plana, N. Gomez, E. Itarte, Unbalanced activation of ERK1/2 and MEK1/2 in apigenin-induced HeLa cell death, Exp. Cell. Res. 299 (2004) 15-26.
64. J.M. Adams, S. Cory, Bcl-2-regulated apoptosis: mechanism and therapeutic potential, Curr. Opin. Immunol. 19 (2007) 488-496.
65. T. Fernandes-Alnemri, G. Litwack, E.S. Alnemri, CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1b-converting enzyme, J. Biol. Chem. 269 (1994) 30761-30764.
66. E.R. Lee, Y.J. Kang, J.H. Kim, H.T. Lee, S.G. Cho, Modulation of apoptosis in HaCaT keratinocytes via differential regulation of ERK signaling pathway by flavonoids, J. Biol. Chem. 280 (2005) 31498-31507;
67. (b) Y. Matsunaga, Y. Kawai, Y. Kohda, M. Gemba, Involvement of activation of NADPH oxidase and extracellular signal-regulated kinase (ERK) in renal cell injury induced by zinc, J. Toxicol. Sci. 30 (2005) 135-144;
68. (c) S. Ramachandiran, Q. Huang, J. Dong, S.S. Lau, T.J. Monks, Mitogen-activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells, Chem. Res. Toxicol. 15 (2002) 1635-1642;
69. (d) X. Zhang, P. Shan, M. Sasidhar, G.L. Chupp, R.A. Flavell, A.M. Choi, P.J. Lee, Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia induced cell death in lung epithelium, Am. J. Resp. Cell. Mol. 28 (2003) 305-315;
70. (e) Y.J. Lee, J.W. Soh, D.I. Jeoung, C.K. Cho, G.J. Jhon, S.J. Lee, Y.S. Lee, PKC epsilon-mediated ERK1/2 activation involved in radiation-induced cell death in NIH3-3 cells, Biochim. Biophys. Acta 1593 (2003) 219-229.
71. K.M. Chan, N.F. Rajab, D. Siegel, L.B. Din, D. Ross, S.H. Inayat-Hussain, Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway, Toxicol. Sci. 116 (2010) 533-548.
72. A. Mishra, J. Wang, Y. Shiozawa, S. McGee, J. Kim, Y. Jung, J. Joseph, J.E. Berry, A. Havens, K.J. Pienta, R.S. Taichman, Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer, Mol. Cancer Res. 10 (2012) 703-715.
73. M.J. Gray, J. Zhang, L.M. Ellis, G.L. Semenza, D.B. Evans, S.S. Watowich, G.E. Gallick, HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas, Oncogene 24 (2005) 3110-3120.
74. P. Büchler, H.A. Reber, M.W. Büchler, H. Friess, R.S. Lavey, O.J. Hines, Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression, Cancer 100 (2004) 201-210.
75. E. Minet, T. Arnould, G. Michel, I. Roland, D. Mottet, M. Raes, J. Remacle, C. Michiels, ERK activation upon hypoxia: involvement in HIF-1 activation, FEBS Lett. 468 (2000) 53-61;
76. (b) K. Williams, R. Cowen, von R. Wasielewski, M. Uenalan, J. Resch, C. West, G. Brabant, HIF-1a is a common downstream target of PI3K and MAPK/ERK signalling in thyroid carcinomas, Endocr. Abstr. 15 (2008) OC39;
77. (c) J. Du, R. Xu, Z. Hu, Y. Tian, Y. Zhu, L. Gu, L. Zhou, PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1a expression in MCF-7 breast cancer cells, PLoS One 6 (2011) e25213;
78. (d) C. Michiels, E. Minet, G. Michel, D. Mottet, J.P. Piret, M. Raes, HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases, IUBMB Life 52 (2001) 49-53.
79. J.D. Gordan, C.B. Thompson, M.C. Simon, HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation, Cancer Cell. 12 (2007) 108-113;
80. (b) J.-W. Kim, P. Gao, Y.-C. Liu, G.L. Semenza, C.V. Dang, Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1, Mol. Cell. Biol. 27 (2007) 7381-7393;
81. (c) K. Podar, K.C. Anderson, A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways, Cell. Cycle 9 (2010) 1722-1730.
82. T. Mosmann, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J. Immunol. Methods 65 (1983) 55-63.