Hypoxia-regulated gene network in drug resistance and cancer progression

Experimental Biology and Medicine

Volumn 239, Issue 7, 2014, Pages 779-792

  Lin, Shao Chieh ^a   Liao, Wan Lin ^a   Lee, Jenq Chang ^a   Tsai, Shaw Jenq ^a  

^a NATIONAL CHENG KUNG UNIVERSITY   (Taiwan)

Author keywords

apoptosis; Drug resistance; hypoxia; metabolic switch; microRNA

Indexed keywords

ABC TRANSPORTER; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; DNA TOPOISOMERASE INHIBITOR; DUAL SPECIFICITY PHOSPHATASE 2; ENDOTHELIN 1; ERYTHROPOIETIN; FIBROBLAST GROWTH FACTOR 9; FRUCTOSE BISPHOSPHATE ALDOLASE; GLUCOSE TRANSPORTER; GLYCERALDEHYDE 3 PHOSPHATE DEHYDROGENASE; HEXOKINASE; HISTONE ACETYLTRANSFERASE PCAF; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MICRORNA; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; MYELOID LEUKEMIA FACTOR 1; PHOSPHOGLYCERATE KINASE; PLATELET DERIVED GROWTH FACTOR B; PYRUVATE DEHYDROGENASE KINASE; PYRUVATE KINASE; SOMATOMEDIN B; SURVIVIN; TRANSFORMING GROWTH FACTOR ALPHA; UBIQUITIN PROTEIN LIGASE E3; UNINDEXED DRUG; VASCULOTROPIN; VON HIPPEL LINDAU PROTEIN;

APOPTOSIS; ARTICLE; B CELL LYMPHOMA; CANCER GROWTH; CELL INVASION; CELL PROLIFERATION; CELL SURVIVAL; DNA DAMAGE; ENZYME INDUCTION; EPITHELIAL MESENCHYMAL TRANSITION; GENE REGULATORY NETWORK; HUMAN; HYPOXIA; LOSS OF FUNCTION MUTATION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; TUMOR SUPPRESSOR GENE;

EID: 84904861737     PISSN: 15353702     EISSN: 15353699     Source Type: Journal    
DOI: 10.1177/1535370214532755     Document Type: Article

References (175)

1. Organization WH. Global status report on noncommunicable diseases 2010, http://www.who.int/nmh/publications/ncd_report2010/en/index.html (2011).
2. Jain RK.Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.Science. 2005;307:58-62.
3. Dewhirst MW,Cao Y,Moeller B.Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response.Nat Rev Cancer. 2008;8:425-37.
4. Semenza GL.Regulation of oxygen homeostasis by hypoxia-inducible factor 1.Physiology (Bethesda). 2009;24:97-106.
5. Wang GL,Jiang BH,Rue EA,Semenza GL.Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.Proc Natl Acad Sci U S A. 1995;92:5510-4.
6. Semenza GL.Targeting HIF-1 for cancer therapy.Nat Rev Cancer. 2003;3:721-32.
7. Keith B,Johnson RS,Simon MC.HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression.Nat Rev Cancer. 2012;12:9-22.
8. Rohwer N,Cramer T.Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways.Drug Resist Updat. 2011;14:191-201.
9. Harris AL.Hypoxia - a key regulatory factor in tumour growth.Nat Rev Cancer. 2002;2:38-47.
10. Nurwidya F,Takahashi F,Minakata K,Murakami A,Takahashi K.From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers.Anat Cell Biol. 2012;45:73-8.
11. Semenza GL.Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.Oncogene. 2010;29:625-34.
12. Wilson WR,Hay MP.Targeting hypoxia in cancer therapy.Nat Rev Cancer. 2011;11:393-410.
13. Wang GL,Semenza GL.General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.Proc Natl Acad Sci U S A. 1993;90:4304-8.
14. Semenza GL,Wang GL.A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.Mol Cell Biol. 1992;12:5447-54.
15. Salceda S,Caro J.Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes.J Biol Chem. 1997;272:22642-7.
16. Huang LE,Gu J,Schau M,Bunn HF.Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.Proc Natl Acad Sci U S A. 1998;95:7987-92.
17. Bruick RK,McKnight SL.A conserved family of prolyl-4-hydroxylases that modify HIF.Science. 2001;294:1337-40.
18. Epstein AC,Gleadle JM,McNeill LA,Hewitson KS,O'Rourke J,Mole DR,Mukherji M,Metzen E,Wilson MI,Dhanda A,Tian YM,Masson N,Hamilton DL,Jaakkola P,Barstead R,Hodgkin J,Maxwell PH,Pugh CW,Schofield CJ,Ratcliffe PJ.C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.Cell. 2001;107:43-54.
19. Jaakkola P,Mole DR,Tian YM,Wilson MI,Gielbert J,Gaskell SJ,von Kriegsheim A,Hebestreit HF,Mukherji M,Schofield CJ,Maxwell PH,Pugh CW,Ratcliffe PJ.Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.Science. 2001;292:468-72.
20. Ivan M,Kondo K,Yang H,Kim W,Valiando J,Ohh M,Salic A,Asara JM,Lane WS,Kaelin WG.HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.Science. 2001;292:464-8.
21. Maxwell PH,Wiesener MS,Chang GW,Clifford SC,Vaux EC,Cockman ME,Wykoff CC,Pugh CW,Maher ER,Ratcliffe PJ.The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Nature. 1999;399:271-5.
22. Luo W,Zhong J,Chang R,Hu H,Pandey A,Semenza GL.Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha.J Biol Chem. 2010;285:3651-63.
23. Ohh M,Park CW,Ivan M,Hoffman MA,Kim TY,Huang LE,Pavletich N,Chau V,Kaelin WG.Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.Nat Cell Biol. 2000;2:423-7.
24. Mahon PC,Hirota K,Semenza GL.FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.Genes Dev. 2001;15:2675-86.
25. Coleman ML,Ratcliffe PJ.Signalling cross talk of the HIF system: involvement of the FIH protein.Curr Pharm Des. 2009;15:3904-7.
26. Ameri K,Hammond EM,Culmsee C,Raida M,Katschinski DM,Wenger RH,Wagner E,Davis RJ,Hai T,Denko N,Harris AL.Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway.Oncogene. 2007;26:284-9.
27. Elvidge GP,Glenny L,Appelhoff RJ,Ratcliffe PJ,Ragoussis J,Gleadle JM.Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways.J Biol Chem. 2006;281:15215-26.
28. Aras S,Pak O,Sommer N,Finley R,Huttemann M,Weissmann N,Grossman LI.Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.Nucleic Acid Res. 2013;41:2255-66.
29. Cummins EP,Comerford KM,Scholz C,Bruning U,Taylor CT.Hypoxic regulation of NF-kappaB signaling.Meth Enzymol. 2007;435:479-92.
30. Koditz J,Nesper J,Wottawa M,Stiehl DP,Camenisch G,Franke C,Myllyharju J,Wenger RH,Katschinski DM.Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor.Blood. 2007;110:3610-7.
31. Mizukami Y,Fujiki K,Duerr EM,Gala M,Jo WS,Zhang X,Chung DC.Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc.J Biol Chem. 2006;281:13957-63.
32. Swanson HI,Yang JH.Specificity of DNA binding of the c-Myc/Max and ARNT/ARNT dimers at the CACGTG recognition site.Nucleic Acid Res. 1999;27:3205-12.
33. Ambrosini G,Nath AK,Sierra-Honigmann MR,Flores-Riveros J.Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1.J Biol Chem. 2002;277:34601-9.
34. Chen KF,Lai YY,Sun HS,Tsai SJ.Transcriptional repression of human cad gene by hypoxia inducible factor-1alpha.Nucleic Acid Res. 2005;33:5190-8.
35. Lu CW,Lin SC,Chen KF,Lai YY,Tsai SJ.Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance.J Biol Chem. 2008;283:28106-14.
36. Ortiz-Barahona A,Villar D,Pescador N,Amigo J,del Peso L.Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction.Nucleic Acids Res. 2010;38:2332-45.
37. Wang HC,Chen YH,Kao HY,Tsai SJ.Inference of transcriptional regulatory network by bootstrapping patterns.Bioinformatics. 2011;27:1422-8.
38. Choi SM,Oh H,Park H.Microarray analyses of hypoxia-regulated genes in an aryl hydrocarbon receptor nuclear translocator (Arnt)-dependent manner.FEBS J. 2008;275:5618-34.
39. Wang V,Davis DA,Haque M,Huang LE,Yarchoan R.Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells.Cancer Res. 2005;65:3299-306.
40. Schodel J,Oikonomopoulos S,Ragoussis J,Pugh CW,Ratcliffe PJ,Mole DR.High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq.Blood. 2011;117:e207-17.
41. Mole DR,Blancher C,Copley RR,Pollard PJ,Gleadle JM,Ragoussis J,Ratcliffe PJ.Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts.J Biol Chem. 2009;284:16767-75.
42. Aprelikova O,Wood M,Tackett S,Chandramouli GV,Barrett JC.Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection.Cancer Res. 2006;66:5641-7.
43. Hu CJ,Wang LY,Chodosh LA,Keith B,Simon MC.Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.Mol Cell Biol. 2003;23:9361-74.
44. Warburg O.über den Stoffwechsel der Carcinomzelle.J Mol Med. 1925;4:534-534.
45. Kim JW,Tchernyshyov I,Semenza GL,Dang CV.HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.Cell Metab. 2006;3:177-85.
46. Papandreou I,Cairns RA,Fontana L,Lim AL,Denko NC.HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.Cell Metab. 2006;3:187-97.
47. Lu CW,Lin SC,Chien CW,Lin SC,Lee CT,Lin BW,Lee JC,Tsai SJ.Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer.Am J Pathol. 2011;179:1405-14.
48. Sivitz WI,Lund DD,Yorek B,Grover-McKay M,Schmid PG.Pretranslational regulation of two cardiac glucose transporters in rats exposed to hypobaric hypoxia.Am J Physiol. 1992;263:E562-9.
49. Firth JD,Ebert BL,Pugh CW,Ratcliffe PJ.Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer.Proc Natl Acad Sci U S A. 1994;91:6496-500.
50. Semenza GL,Roth PH,Fang HM,Wang GL.Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.J Biol Chem. 1994;269:23757-63.
51. Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009;324:1029-33.
52. Hensley CT,Wasti AT,DeBerardinis RJ.Glutamine and cancer: cell biology, physiology, and clinical opportunities.J Clin Invest. 2013;123:3678-84.
53. Topkan E,Parlak C,Topuk S,Pehlivan B.Influence of oral glutamine supplementation on survival outcomes of patients treated with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer.BMC Cancer. 2012;12:502-502.
54. Gao P,Tchernyshyov I,Chang TC,Lee YS,Kita K,Ochi T,Zeller KI,De Marzo AM,Van Eyk JE,Mendell JT,Dang CV.c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.Nature. 2009;458:762-5.
55. Liu W,Le A,Hancock C,Lane AN,Dang CV,Fan TW,Phang JM.Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC.Proc Natl Acad Sci U S A. 2012;109:8983-8.
56. Pinheiro C,Longatto-Filho A,Azevedo-Silva J,Casal M,Schmitt FC,Baltazar F.Role of monocarboxylate transporters in human cancers: state of the art.J Bioenerg Biomembr. 2012;44:127-39.
57. Chiche J,Brahimi-Horn MC,Pouyssegur J.Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.J Cell Mol Med. 2010;14:771-94.
58. Swietach P,Wigfield S,Cobden P,Supuran CT,Harris AL,Vaughan-Jones RD.Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths.J Biol Chem. 2008;283:20473-83.
59. Feldser D,Agani F,Iyer NV,Pak B,Ferreira G,Semenza GL.Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2.Cancer Res. 1999;59:3915-8.
60. Forsythe JA,Jiang BH,Iyer NV,Agani F,Leung SW,Koos RD,Semenza GL.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol. 1996;16:4604-13.
61. Grimshaw MJ.Endothelins and hypoxia-inducible factor in cancer.Endocr Relat Cancer. 2007;14:233-44.
62. Szenajch J,Wcislo G,Jeong JY,Szczylik C,Feldman L.The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells From clinic to bench - a critical review.Biochim Biophys Acta. 2010;1806:82-95.
63. Chen TM,Shih YH,Tseng JT,Lai MC,Wu CH,Li YH,Tsai SJ,Sun HS.Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation.Nucleic Acids Res. 2013;:.
64. Braunstein S,Karpisheva K,Pola C,Goldberg J,Hochman T,Yee H,Cangiarella J,Arju R,Formenti SC,Schneider RJ.A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer.Molecular Cell. 2007;28:501-12.
65. Uniacke J,Holterman CE,Lachance G,Franovic A,Jacob MD,Fabian MR,Payette J,Holcik M,Pause A,Lee S.An oxygen-regulated switch in the protein synthesis machinery.Nature. 2012;486:126-9.
66. Lin SC,Chien CW,Lee JC,Yeh YC,Hsu KF,Lai YY,Lin SC,Tsai SJ.Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells.J Clin Invest. 2011;121:1905-16.
67. Chen N,Chen X,Huang R,Zeng H,Gong J,Meng W,Lu Y,Zhao F,Wang L,Zhou Q.BCL-xL is a target gene regulated by hypoxia-inducible factor-1{alpha}.J Biol Chem. 2009;284:10004-12.
68. Erler JT,Cawthorne CJ,Williams KJ,Koritzinsky M,Wouters BG,Wilson C,Miller C,Demonacos C,Stratford IJ,Dive C.Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance.Mol Cell Biol. 2004;24:2875-89.
69. Townsend KN,Hughson LR,Schlie K,Poon VI,Westerback A,Lum JJ.Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity.Immunol Rev. 2012;249:176-94.
70. Eng CH,Abraham RT.The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming.Oncogene. 2011;30:4687-96.
71. Zhang H,Bosch-Marce M,Shimoda LA,Tan YS,Baek JH,Wesley JB,Gonzalez FJ,Semenza GL.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.J Biol Chem. 2008;283:10892-903.
72. Bellot G,Garcia-Medina R,Gounon P,Chiche J,Roux D,Pouyssegur J,Mazure NM.Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.Mol Cell Biol. 2009;29:2570-81.
73. Shweiki D,Itin A,Soffer D,Keshet E.Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature. 1992;359:843-5.
74. Cao Y,Linden P,Shima D,Browne F,Folkman J.In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor.J Clin Invest. 1996;98:2507-11.
75. Semenza GL.Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis.Oncogene. 2013;32:4057-63.
76. Khong TL,Thairu N,Larsen H,Dawson PM,Kiriakidis S,Paleolog EM.Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer.BMC Cancer. 2013;13:518.-518.
77. Pan J,Mestas J,Burdick MD,Phillips RJ,Thomas GV,Reckamp K,Belperio JA,Strieter RM.Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis.Mol Cancer. 2006;5:56-56.
78. von Minckwitz G,Eidtmann H,Rezai M,Fasching PA,Tesch H,Eggemann H,Schrader I,Kittel K,Hanusch C,Kreienberg R,Solbach C,Gerber B,Jackisch C,Kunz G,Blohmer JU,Huober J,Hauschild M,Fehm T,Muller BM,Denkert C,Loibl S,Nekljudova V,Untch M.Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.N Engl J Med. 2012;366:299-309.
79. Tol J,Koopman M,Cats A,Rodenburg CJ,Creemers GJ,Schrama JG,Erdkamp FL,Vos AH,van Groeningen CJ,Sinnige HA,Richel DJ,Voest EE,Dijkstra JR,Vink-Borger ME,Antonini NF,Mol L,van Krieken JH,Dalesio O,Punt CJ.Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer.N Engl J Med. 2009;360:563-72.
80. Custodio A,Barriuso J,de Castro J,Martinez-Marin V,Moreno V,Rodriguez-Salas N,Feliu J.Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives.Cancer Treat Rev. 2013;39:908-24.
81. Tol J,Punt CJ.Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review.Clin Ther. 2010;32:437-53.
82. Tsai YP,Wu KJ.Hypoxia-regulated target genes implicated in tumor metastasis.J Biomed Sci. 2012;19:102-102.
83. Yang MH,Wu MZ,Chiou SH,Chen PM,Chang SY,Liu CJ,Teng SC,Wu KJ.Direct regulation of TWIST by HIF-1alpha promotes metastasis.Nat Cell Biol. 2008;10:295-305.
84. Peinado H,Olmeda D,Cano A.Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?.Nat Rev Cancer. 2007;7:415-28.
85. Imai T,Horiuchi A,Wang C,Oka K,Ohira S,Nikaido T,Konishi I.Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells.Am J Pathol. 2003;163:1437-47.
86. Stipp CS,Kolesnikova TV,Hemler ME.Functional domains in tetraspanin proteins.Trends Biochem Sci. 2003;28:106-12.
87. Chien C-W,Lin S-C,Lai Y-Y,Lin B-W,Lin S-C,Lee J-C,Tsai S-J.Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer.Clin Cancer Res. 2008;14:8043-51.
88. Erler JT,Bennewith KL,Nicolau M,Dornhofer N,Kong C,Le QT,Chi JT,Jeffrey SS,Giaccia AJ.Lysyl oxidase is essential for hypoxia-induced metastasis.Nature. 2006;440:1222-6.
89. Lin JL,Wang MJ,Lee D,Liang CC,Lin S.Hypoxia-inducible factor-1alpha regulates matrix metalloproteinase-1 activity in human bone marrow-derived mesenchymal stem cells.FEBS Lett. 2008;582:2615-9.
90. Petrella BL,Lohi J,Brinckerhoff CE.Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma.Oncogene. 2005;24:1043-52.
91. Zhang H,Wong CC,Wei H,Gilkes DM,Korangath P,Chaturvedi P,Schito L,Chen J,Krishnamachary B,Winnard PT,Raman V,Zhen L,Mitzner WA,Sukumar S,Semenza GL.HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.Oncogene. 2012;31:1757-70.
92. Gatenby RA,Smallbone K,Maini PK,Rose F,Averill J,Nagle RB,Worrall L,Gillies RJ.Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer.Br J Cancer. 2007;97:646-53.
93. Lee RC,Feinbaum RL,Ambros V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993;75:843-54.
94. Iorio MV,Croce CM.MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review.EMBO Mol Med. 2012;4:143-59.
95. Bao B,Azmi AS,Ali S,Ahmad A,Li Y,Banerjee S,Kong D,Sarkar FH.The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness.Biochim Biophys Acta. 2012;1826:272-96.
96. Liao WL, Lin SC, S. SH, Tsai SJ. Hypoxia-induced tumor malignancy and drug resistance: Role of microRNAs. Biomarker Genomic Med 2014;6:1-11.
97. Bristow RG,Hill RP.Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability.Nat Rev Cancer. 2008;8:180-92.
98. Nurwidya F,Takahashi F,Minakata K,Murakami A,Takahashi K.From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers.Anatomy Cell Biol. 2012;45:73-73.
99. Kondoh H.Cellular life span and the Warburg effect.Exp Cell Res. 2008;314:1923-8.
100. Brizel DM,Sibley GS,Prosnitz LR,Scher RL,Dewhirst MW.Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.Int J Radiat Oncol Biol Phys. 1997;38:285-9.
101. Zhang H,Gao P,Fukuda R,Kumar G,Krishnamachary B,Zeller KI,Dang CV,Semenza GL.HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.Cancer Cell. 2007;11:407-20.
102. Fruehauf JP,Meyskens FL.Reactive oxygen species: a breath of life or death?.Clin Cancer Res. 2007;13:789-94.
103. Rohwer N,Dame C,Haugstetter A,Wiedenmann B,Detjen K,Schmitt CA,Cramer T.Hypoxia-inducible factor 1alpha determines gastric cancer chemosensitivity via modulation of p53 and NF-kappaB.PLoS One. 2010;5:e12038-e12038.
104. Comerford KM,Wallace TJ,Karhausen J,Louis NA,Montalto MC,Colgan SP.Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.Cancer Res. 2002;62:3387-94.
105. Ding Z,Yang L,Xie X,Xie F,Pan F,Li J,He J,Liang H.Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells.J Cancer Res Clin Oncol. 2010;136:1697-707.
106. Liu L,Ning X,Sun L,Zhang H,Shi Y,Guo C,Han S,Liu J,Sun S,Han Z,Wu K,Fan D.Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer.Cancer Sci. 2008;99:121-8.
107. Li J,Shi M,Cao Y,Yuan W,Pang T,Li B,Sun Z,Chen L,Zhao RC.Knockdown of hypoxia-inducible factor-1alpha in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate.Biochem Biophys Res Commun. 2006;342:1341-51.
108. Nardinocchi L,Puca R,Sacchi A,D'Orazi G.Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis.Mol Cancer. 2009;8:1-1.
109. Zhu H,Chen XP,Luo SF,Guan J,Zhang WG,Zhang BX.Involvement of hypoxia-inducible factor-1-alpha in multidrug resistance induced by hypoxia in HepG2 cells.J Exp Clin Cancer Res. 2005;24:565-74.
110. Chen L,Feng P,Li S,Long D,Cheng J,Lu Y,Zhou D.Effect of hypoxia-inducible factor-1alpha silencing on the sensitivity of human brain glioma cells to doxorubicin and etoposide.Neurochem Res. 2009;34:984-90.
111. Abdulkadir SA,Qu Z,Garabedian E,Song SK,Peters TJ,Svaren J,Carbone JM,Naughton CK,Catalona WJ,Ackerman JJ,Gordon JI,Humphrey PA,Milbrandt J.Impaired prostate tumorigenesis in Egr1-deficient mice.Nat Med. 2001;7:101-7.
112. Ma J,Ren Z,Ma Y,Xu L,Zhao Y,Zheng C,Fang Y,Xue T,Sun B,Xiao W.Targeted knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated invasion of prostate cancer cells through suppressing EGR-1/NF-kappaB synergy.J Biol Chem. 2009;284:34600-6.
113. Mahalingam D,Natoni A,Keane M,Samali A,Szegezdi E.Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells.Br J Cancer. 2010;102:754-64.
114. Shiloh Y.The ATM-mediated DNA-damage response: taking shape.Trends Biochem Sci. 2006;31:402-10.
115. Hammond EM,Denko NC,Dorie MJ,Abraham RT,Giaccia AJ.Hypoxia links ATR and p53 through replication arrest.Mol Cell Biol. 2002;22:1834-43.
116. Green SL,Giaccia AJ.Tumor hypoxia and the cell cycle: implications for malignant progression and response to therapy.Cancer J Sci Am. 1998;4:218-23.
117. Yamamoto T,Ebisuya M,Ashida F,Okamoto K,Yonehara S,Nishida E.Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell-cycle progression.Curr Biol. 2006;16:1171-82.
118. Brunet A,Roux D,Lenormand P,Dowd S,Keyse S,Pouyssegur J.Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry.EMBO J. 1999;18:664-74.
119. Gioeli D,Mandell JW,Petroni GR,Frierson HF,Weber MJ.Activation of mitogen-activated protein kinase associated with prostate cancer progression.Cancer Res. 1999;59:279-84.
120. Hoshino R,Chatani Y,Yamori T,Tsuruo T,Oka H,Yoshida O,Shimada Y,Ari-i S,Wada H,Fujimoto J,Kohno M.Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors.Oncogene. 1999;18:813-22.
121. Sebolt-Leopold JS,Dudley DT,Herrera R,Van Becelaere K,Wiland A,Gowan RC,Tecle H,Barrett SD,Bridges A,Przybranowski S,Leopold WR,Saltiel AR.Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.Nat Med. 1999;5:810-6.
122. Kohno M,Pouyssegur J.Targeting the ERK signaling pathway in cancer therapy.Ann Med. 2006;38:200-11.
123. Paez JG,Janne PA,Lee JC,Tracy S,Greulich H,Gabriel S,Herman P,Kaye FJ,Lindeman N,Boggon TJ,Naoki K,Sasaki H,Fujii Y,Eck MJ,Sellers WR,Johnson BE,Meyerson M.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004;304:1497-500.
124. Downward J.Targeting RAS signalling pathways in cancer therapy.Nat Rev. 2003;3:11-22.
125. Davies H,Bignell GR,Cox C,Stephens P,Edkins S,Clegg S,Teague J,Woffendin H,Garnett MJ,Bottomley W,Davis N,Dicks E,Ewing R,Floyd Y,Gray K,Hall S,Hawes R,Hughes J,Kosmidou V,Menzies A,Mould C,Parker A,Stevens C,Watt S,Hooper S,Wilson R,Jayatilake H,Gusterson BA,Cooper C,Shipley J,Hargrave D,Pritchard-Jones K,Maitland N,Chenevix-Trench G,Riggins GJ,Bigner DD,Palmieri G,Cossu A,Flanagan A,Nicholson A,Ho JW,Leung SY,Yuen ST,Weber BL,Seigler HF,Darrow TL,Paterson H,Marais R,Marshall CJ,Wooster R,Stratton MR,Futreal PA.Mutations of the BRAF gene in human cancer.Nature. 2002;417:949-54.
126. Wan PT,Garnett MJ,Roe SM,Lee S,Niculescu-Duvaz D,Good VM,Jones CM,Marshall CJ,Springer CJ,Barford D,Marais R.Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.Cell. 2004;116:855-67.
127. McCubrey JA,Steelman LS,Chappell WH,Abrams SL,Wong EW,Chang F,Lehmann B,Terrian DM,Milella M,Tafuri A,Stivala F,Libra M,Basecke J,Evangelisti C,Martelli AM,Franklin RA.Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.Biochimica et biophysica acta. 2007;1773:1263-84.
128. Persons DL,Yazlovitskaya EM,Cui W,Pelling JC.Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin.Clin Cancer Res. 1999;5:1007-14.
129. Fan M,Chambers TC.Role of mitogen-activated protein kinases in the response of tumor cells to chemotherapy.Drug Resist Updat. 2001;4:253-67.
130. Oka H,Chatani Y,Hoshino R,Ogawa O,Kakehi Y,Terachi T,Okada Y,Kawaichi M,Kohno M,Yoshida O.Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma.Cancer Res. 1995;55:4182-7.
131. Balko JM,Cook RS,Vaught DB,Kuba MG,Miller TW,Bhola NE,Sanders ME,Granja-Ingram NM,Smith JJ,Meszoely IM,Salter J,Dowsett M,Stemke-Hale K,Gonzalez-Angulo AM,Mills GB,Pinto JA,Gomez HL,Arteaga CL.Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance.Nat Med. 2012;18:1052-9.
132. Balko JM,Schwarz LJ,Bhola NE,Kurupi R,Owens P,Miller TW,Gomez H,Cook RS,Arteaga CL.Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.Cancer Res. 2013;73:6346-58.
133. Dong D,Ko B,Baumeister P,Swenson S,Costa F,Markland F,Stiles C,Patterson JB,Bates SE,Lee AS.Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment.Cancer Res. 2005;65:5785-91.
134. Lin MT,Chang CC,Chen ST,Chang HL,Su JL,Chau YP,Kuo ML.Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP up-regulation.J Biol Chem. 2004;279:24015-23.
135. Ohashi R,Tajima K,Takahashi F,Cui R,Gu T,Shimizu K,Nishio K,Fukuoka K,Nakano T,Takahashi K.Osteopontin modulates malignant pleural mesothelioma cell functions in vitro.Anticancer Res. 2009;29:2205-14.
136. Ahn GO,Botting KJ,Patterson AV,Ware DC,Tercel M,Wilson WR.Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug of a chloromethylbenzindoline DNA minor groove alkylator.Biochem Pharmacol. 2006;71:1683-94.
137. Brown JM.SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours.Br J Cancer. 1993;67:1163-70.
138. Chowdhury G,Junnotula V,Daniels JS,Greenberg MM,Gates KS.DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O(2).J Am Chem Soc. 2007;129:12870-7.
139. Patterson LH.Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent.Cancer Metastasis Rev. 1993;12:119-34.
140. Shinde SS,Hay MP,Patterson AV,Denny WA,Anderson RF.Spin trapping of radicals other than the *OH radical upon reduction of the anticancer agent tirapazamine by cytochrome P450 reductase.J Am Chem Soc. 2009;131:14220-1.
141. Weiss GJ,Infante JR,Chiorean EG,Borad MJ,Bendell JC,Molina JR,Tibes R,Ramanathan RK,Lewandowski K,Jones SF,Lacouture ME,Langmuir VK,Lee H,Kroll S,Burris HA.Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies.Clin Cancer Res. 2011;17:2997-3004.
142. Wilson WR,Van Zijl P,Denny WA.Bis-bioreductive agents as hypoxia-selective cytotoxins: nitracrine N-oxide.Int J Radiat Oncol Biol Phys. 1992;22:693-6.
143. Hudson CC,Liu M,Chiang GG,Otterness DM,Loomis DC,Kaper F,Giaccia AJ,Abraham RT.Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin.Mol Cell Biol. 2002;22:7004-14.
144. Ohtsu A,Ajani JA,Bai YX,Bang YJ,Chung HC,Pan HM,Sahmoud T,Shen L,Yeh KH,Chin K,Muro K,Kim YH,Ferry D,Tebbutt NC,Al-Batran SE,Smith H,Costantini C,Rizvi S,Lebwohl D,Van Cutsem E.Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study.J Clin Oncol. 2013;31:3935-43.
145. Kruczek K,Ratterman M,Tolzien K,Sulo S,Lestingi TM,Nabhan C.A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer.Br J Cancer. 2013;109:1711-6.
146. Yu K,Shi C,Toral-Barza L,Lucas J,Shor B,Kim JE,Zhang WG,Mahoney R,Gaydos C,Tardio L,Kim SK,Conant R,Curran K,Kaplan J,Verheijen J,Ayral-Kaloustian S,Mansour TS,Abraham RT,Zask A,Gibbons JJ.Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.Cancer Res. 2010;70:621-31.
147. Rapisarda A,Shoemaker RH,Melillo G.Targeting topoisomerase I to inhibit hypoxia inducible factor 1.Cell Cycle. 2004;3:172-5.
148. Vergote IB,Garcia A,Micha J,Pippitt C,Bendell J,Spitz D,Reed N,Dark G,Fracasso PM,Ibrahim EN,Armenio VA,Duska L,Poole C,Gennigens C,Dirix LY,Leung AC,Zhao C,Soufi-Mahjoubi R,Rustin G.Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer.J Clin Oncol. 2013;31:4060-6.
149. Tanaka T,Yamaguchi J,Shoji K,Nangaku M.Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host.J Biol Chem. 2012;287:34866-82.
150. Moroney J,Fu S,Moulder S,Falchook G,Helgason T,Levenback C,Hong D,Naing A,Wheler J,Kurzrock R.Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity.Clin Cancer Res. 2012;18:5796-805.
151. Mabjeesh NJ,Escuin D,LaVallee TM,Pribluda VS,Swartz GM,Johnson MS,Willard MT,Zhong H,Simons JW,Giannakakou P.2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.Cancer Cell. 2003;3:363-75.
152. Lopez-Lazaro M.Digoxin, HIF-1, and cancer.Proc Natl Acad Sci U S A. 2009;106:.
153. Isaacs JS,Jung YJ,Mimnaugh EG,Martinez A,Cuttitta F,Neckers LM.Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway.J Biol Chem. 2002;277:29936-44.
154. Modi S,Stopeck AT,Gordon MS,Mendelson D,Solit DB,Bagatell R,Ma W,Wheler J,Rosen N,Norton L,Cropp GF,Johnson RG,Hannah AL,Hudis CA.Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study.J Clin Oncol. 2007;25:5410-7.
155. de Bono JS,Kristeleit R,Tolcher A,Fong P,Pacey S,Karavasilis V,Mita M,Shaw H,Workman P,Kaye S,Rowinsky EK,Aherne W,Atadja P,Scott JW,Patnaik A.Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors.Clin Cancer Res. 2008;14:6663-73.
156. Harrison SJ,Quach H,Link E,Seymour JF,Ritchie DS,Ruell S,Dean J,Januszewicz H,Johnstone R,Neeson P,Dickinson M,Nichols J,Prince HM.A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma.Blood. 2011;118:6274-83.
157. Coiffier B,Pro B,Prince HM,Foss F,Sokol L,Greenwood M,Caballero D,Borchmann P,Morschhauser F,Wilhelm M,Pinter-Brown L,Padmanabhan S,Shustov A,Nichols J,Carroll S,Balser J,Balser B,Horwitz S.Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy.J Clin Oncol. 2012;30:631-6.
158. Chun YS,Yeo EJ,Park JW.Versatile pharmacological actions of YC-1: anti-platelet to anticancer.Cancer Lett. 2004;207:1-7.
159. Li SH,Shin DH,Chun YS,Lee MK,Kim MS,Park JW.A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}.Mol Cancer Ther. 2008;7:3729-38.
160. Lee K,Zhang H,Qian DZ,Rey S,Liu JO,Semenza GL.Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization.Proc Natl Acad Sci U S A. 2009;106:17910-5.
161. Watanabe K,Oguri H,Oikawa H.Diversification of echinomycin molecular structure by way of chemoenzymatic synthesis and heterologous expression of the engineered echinomycin biosynthetic pathway.Curr Opin Chem Biol. 2009;13:189-96.
162. Cook KM,Hilton ST,Mecinovic J,Motherwell WB,Figg WD,Schofield CJ.Epidithiodiketopiperazines block the interaction between hypoxia-inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism.J Biol Chem. 2009;284:26831-8.
163. Ramanathan RK,Kirkpatrick DL,Belani CP,Friedland D,Green SB,Chow HH,Cordova CA,Stratton SP,Sharlow ER,Baker A,Dragovich T.A Phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors.Clin Cancer Res. 2007;13:2109-14.
164. Kaluz S,Kaluzova M,Stanbridge EJ.Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain.Mol Cell Biol. 2006;26:5895-907.
165. Gay F,Magarotto V,Crippa C,Pescosta N,Guglielmelli T,Cavallo F,Pezzatti S,Ferrari S,Liberati AM,Oliva S,Patriarca F,Offidani M,Omede P,Montefusco V,Petrucci MT,Giuliani N,Passera R,Pietrantuono G,Boccadoro M,Corradini P,Palumbo A.Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results.Blood. 2013;122:1376-83.
166. Yeo EJ,Ryu JH,Cho YS,Chun YS,Huang LE,Kim MS,Park JW.Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1.Blood. 2006;107:916-23.
167. Ciuleanu TE,Pavlovsky AV,Bodoky G,Garin AM,Langmuir VK,Kroll S,Tidmarsh GT.A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine.Eur J Cancer. 2009;45:1589-96.
168. Wood TE,Dalili S,Simpson CD,Hurren R,Mao X,Saiz FS,Gronda M,Eberhard Y,Minden MD,Bilan PJ,Klip A,Batey RA,Schimmer AD.A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death.Mol Cancer Ther. 2008;7:3546-55.
169. Sonveaux P,Vegran F,Schroeder T,Wergin MC,Verrax J,Rabbani ZN,De Saedeleer CJ,Kennedy KM,Diepart C,Jordan BF,Kelley MJ,Gallez B,Wahl ML,Feron O,Dewhirst MW.Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.J Clin Invest. 2008;118:3930-42.
170. Goel HL,Mercurio AM.VEGF targets the tumour cell.Nat Rev Cancer. 2013;13:871-82.
171. Hurwitz H,Fehrenbacher L,Novotny W,Cartwright T,Hainsworth J,Heim W,Berlin J,Baron A,Griffing S,Holmgren E,Ferrara N,Fyfe G,Rogers B,Ross R,Kabbinavar F.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004;350:2335-42.
172. Kolch W,Pitt A.Functional proteomics to dissect tyrosine kinase signalling pathways in cancer.Nat Rev Cancer. 2010;10:618-29.
173. Jonker DJ,O'Callaghan CJ,Karapetis CS,Zalcberg JR,Tu D,Au HJ,Berry SR,Krahn M,Price T,Simes RJ,Tebbutt NC,van Hazel G,Wierzbicki R,Langer C,Moore MJ.Cetuximab for the treatment of colorectal cancer.N Engl J Med. 2007;357:2040-8.
174. Flaherty KT,Infante JR,Daud A,Gonzalez R,Kefford RF,Sosman J,Hamid O,Schuchter L,Cebon J,Ibrahim N,Kudchadkar R,Burris HA,3rd, Falchook G,Algazi A,Lewis K,Long GV,Puzanov I,Lebowitz P,Singh A,Little S,Sun P,Allred A,Ouellet D,Kim KB,Patel K,Weber J.Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.N Engl J Med. 2012;367:1694-703.
175. Arber N,Eagle CJ,Spicak J,Racz I,Dite P,Hajer J,Zavoral M,Lechuga MJ,Gerletti P,Tang J,Rosenstein RB,Macdonald K,Bhadra P,Fowler R,Wittes J,Zauber AG,Solomon SD,Levin B.Celecoxib for the prevention of colorectal adenomatous polyps.N Engl J Med. 2006;355:885-95.