Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects

Clinical and Experimental Pharmacology and Physiology

Volumn 40, Issue 5, 2013, Pages 307-319

  Wong, Mei S ^a   Sidik, Shiran M ^a   Mahmud, Rozi ^a   Stanslas, Johnson ^a  

^a UNIVERSITY PUTRA MALAYSIA   (Malaysia)

Author keywords

C Met kinase inhibitors; C Src kinase inhibitors; Invasion; Matrix metalloproteinases inhibitors; Metastasis; Receptor tyrosine kinase inhibitors

Indexed keywords

17AAG; 2 [[(4 PHENOXYPHENYL)SULFONYL]METHYL]THIIRANE; 2 MORPHOLINO 8 PHENYLCHROMONE; 5 [(5 FLUORO 1,2 DIHYDRO 2 OXO 3H INDOL 3 YLIDENE)METHYL] N (2 HYDROXY 3 MORPHOLINOPROPYL) 2,4 DIMETHYL 1H PYRROLE 3 CARBOXAMIDE; ANTIMETASTATIC AGENT; BEVACIZUMAB; BOSUTINIB; CRIZOTINIB; DASATINIB; DEMETHOXYVIRIDIN; FLUOROURACIL; FOLINIC ACID; FORETINIB; IMATINIB; IRINOTECAN; JNJ 38877605; MARIMASTAT; MMI 166; N (3 CHLOROPHENYL) 3 [3,5 DIMETHYL 4 (4 METHYL 1 PIPERAZINYLCARBONYL) 1H PYRROL 2 YLMETHYLENE] 2,3 DIHYDRO N METHYL 2 OXO 1H INDOLE 5 SULFONAMIDE; PHA 66752; PRINOMASTAT; RAPAMYCIN; S 3304; SARACATINIB; SEMAXANIB; TANOMASTAT; TIVANTINIB; UK 356202; UNCLASSIFIED DRUG; UNINDEXED DRUG; WF 536; WORTMANNIN; WX UK 1;

ANGIOGENESIS; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CELL CYCLE PROGRESSION; CELL MOTILITY; CELL PROLIFERATION; CELL SURFACE; CELL SURVIVAL; CHEMOTAXIS; COLORECTAL CANCER; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; HUMAN; LUNG NON SMALL CELL CANCER; LYMPHANGIOGENESIS; METASTASIS; METASTASIS INHIBITION; METASTASIS POTENTIAL; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; MUSCULOSKELETAL DISEASE; ONCOGENE SRC; PRIMARY TUMOR; REVIEW; SIGNAL TRANSDUCTION; TUMOR INVASION;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; BIOMEDICAL RESEARCH; DRUG DISCOVERY; DRUG INDUSTRY; DRUGS, INVESTIGATIONAL; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOPLASM PROTEINS; NEOVASCULARIZATION, PATHOLOGIC; SIGNAL TRANSDUCTION;

EID: 84876882865     PISSN: 03051870     EISSN: 14401681     Source Type: Journal    
DOI: 10.1111/1440-1681.12083     Document Type: Review

References (155)

1. Zetter BR. Angiogenesis and tumor metastasis. Annu. Rev. Med. 1998; 49: 407-24.
2. Weiss L. Metastatic inefficiency. Adv. Cancer Res. 1990; 54: 159-211.
3. Nannuru K, Singh R. Tumor-stromal interactions in bone metastasis. Curr. Osteoporos. Rep. 2010; 8: 105-13.
4. Le NH, Franken P, Fodde R. Tumour-stroma interactions in colorectal cancer: Converging on beta-catenin activation and cancer stemness. Br. J. Cancer 2008; 98: 1886-93.
5. Gupta GP, Massagué J. Cancer metastasis: Building a framework. Cell 2006; 127: 679-95.
6. Eccles SA, Welch DR. Metastasis: Recent discoveries and novel treatment strategies. Lancet 2007; 369: 1742-57.
7. Fidler I, Hart IR. Biological diversity in metastatic neoplasms: Origins and implications. Science 1982; 217: 998-1001.
8. Bernards R, Weinberg RA. Metastasis genes: A progression puzzle. Nature 2002; 418: 823.
9. Naiki T, Asamoto M, Toyoda-Hokaiwado N et al. Organ specific Gst-pi expression of the metastatic androgen independent prostate cancer cells in nude mice. Prostate 2012; 72: 533-41.
10. Zlotnik A, Burkhardt AM, Homey B. Homeostatic chemokine receptors and organ-specific metastasis. Nat. Rev. Immunol. 2011; 11: 597-606.
11. Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer 1997; 80: 1529-37.
12. Wong CW, Lee A, Shientag L et al. Apoptosis: An early event in metastatic inefficiency. Cancer Res. 2001; 61: 338.
13. Louderbough JM, Brown JA, Nagle RB, Schroeder JA. CD44 Promotes epithelial mammary gland development and exhibits altered localization during cancer progression. Genes Cancer 2011; 2: 771-81.
14. Rahimi N, Rezazadeh K, Mahoney JE, Hartsough E, Meyer RD. Identification of IGPR-1 as a novel adhesion molecule involved in angiogenesis. Mol. Biol. Cell 2012; 23: 1646-56.
15. Justilien V, Regala RP, Tseng IC et al. Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS one 2012; 7: e35040.
16. Sung BH, Weaver AM. Regulation of lysosomal secretion by cortactin drives fibronectin deposition and cell motility. Bioarchitecture 2011; 1: 257-60.
17. Paget S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1989; 8: 98-101.
18. Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. CancerBiol. 2004; 14: 171-9.
19. Oppenheimer SB. Cellular basis of cancer metastasis: A review of fundamentals and new advances. Acta Histochem. 2006; 108: 327-34.
20. Kaplan RN, Riba RD, Zacharoulis S et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438: 820-7.
21. Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat. Rev. Cancer 2002; 2: 38-47.
22. Erler JT, Bennewith KL, Nicolau M et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440: 1222-6.
23. Friedl P, Wolf K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat. Rev. Cancer 2003; 3: 362-74.
24. Frisch SM, Screaton RA. Anoikis mechanisms. Curr. Opin. Cell Biol. 2001; 13: 555-62.
25. Townson JL, Naumov GN, Chambers AF. The role of apoptosis in tumor progression and metastasis. Curr. Mol. Med. 2003; 3: 631-42.
26. Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis 2005; 26: 703-11.
27. Wicha MS, Liu S, Dontu G. Cancer stem cells: An old idea-a paradigm shift. Cancer Res. 2006; 66: 1883-90.
28. Hirschmann-Jax C, Foster AE, Wulf GG et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc. Natl Acad. Sci. USA 2004; 101: 14228-33.
29. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005; 5: 275-84.
30. Androutsellis-Theotokis A, Leker RR, Soldner F et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442: 823-6.
31. Liu S, Dontu G, Mantle ID et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006; 66: 6063-71.
32. Patyna S, Laird AD, Mendel DB et al. SU14813: A novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol. Cancer Ther. 2006; 5: 1774-82.
33. Fiedler W, Giaccone G, Lasch P et al. Phase I trial of SU14813 in patients with advanced solid malignancies. Ann. Oncol. 2011; 22: 195-201.
34. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: Structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003; 22: 309-25.
35. Hou J, Dong J, Sun L et al. Inhibition of phosphorylated c-Met in rhabdomyosarcoma cell lines by a small molecule inhibitor SU11274. J. Transl. Med. 2011; 9: 64.
36. Inagaki Y, Qi F, Gao J et al. Effect of c-Met inhibitor SU11274 on hepatocellular carcinoma cell growth. Biosci. Trends 2011; 5: 52-6.
37. Zou HY, Li Q, Lee JH et al. Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor. Mol. Cancer. Ther. 2012; 11: 1036-47.
38. Broxterman HJ, Georgopapadakou NH. Anticancer therapeutics: A surge of new developments increasingly target tumor and stroma. Drug Resis. Updat. 2007; 10: 182-93.
39. Shaw AT, Yeap BY, Solomon BJ et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: A retrospective analysis. Lancet Oncol. 2011; 12: 1004-12.
40. Adjei AA, Schwartz B, Garmey E. Early Clinical Development of ARQ 197, a selective, non-ATP-Competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist 2011; 16: 788-99.
41. Sequist LV, von Pawel J, Garmey EG et al. Randomized phase II study of erlotinib Plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 2011; 29: 3307-15.
42. Zillhardt M, Park S-M, Romero IL et al. Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin. Cancer Res. 2011; 17: 4042-51.
43. Eder JP, Shapiro GI, Appleman LJ et al. A phase I study of foretinib, a Multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin. Cancer Res. 2010; 16: 3507-16.
44. Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316: 1039-43.
45. Nardi Va, Azam Ma, Daley Gqb. Mechanisms and implications of imatinib resistance mutations in BCR-ABL. Curr. Opin. Hematol. 2004; 11: 35-43.
46. Mohi MG, Boulton C, Gu T-L et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl Acad. Sci. USA 2004; 101: 3130-5.
47. Stern M, Herrmann R. Overview of monoclonal antibodies in cancer therapy: Present and promise. Crit. Rev. Oncol. Hematol. 2005; 54: 11-29.
48. Carmeliet P. Angiogenesis in health and disease. Nat. Med. 2003; 9: 653-60.
49. Apte SM, Fan D, Killion JJ, Fidler IJ. Targeting the platelet-derived growth factor receptor in antivascular therapy for human ovarian carcinoma. Clin. Cancer Res. 2004; 10: 897-908.
50. Rosen LS. Clinical experience with angiogenesis signaling inhibitors: Focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 2002; 9: 36-44.
51. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 2004; 350: 2335-42.
52. Giantonio BJ. Bevacizumab in the treatment of metastatic colorectal cancer (mCRC) in second- and third-line settings. Semin. Oncol. 2006; 33: S15-S18.
53. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 2006; 355: 2542-50.
54. Manetti F, Botta M. Small-molecule inhibitors of fibroblast growth factor receptor (FGFR) tyrosine kinases (TK). Curr. Pharm. Des. 2003; 9: 567-81.
55. Fong TAT, Shawver LK, Sun L et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999; 59: 99-106.
56. Noguera-Troise I, Daly C, Papadopoulos NJ et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006; 444: 1032-7.
57. Ridgway J, Zhang G, Wu Y et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006; 444: 1083-7.
58. Orlichenko L, Radisky D. Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin. Exp. Metastasis 2008; 25: 593-600.
59. Overall CM. Dilating the degradome: Matrix metalloproteinase 2 (MMP-2) cuts to the heart of the matter. Biochem. J. 2004; 383: e5-7.
60. Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nat. Rev. Cancer 2002; 2: 657-72.
61. Chang MC, Chen CA, Chen PJ et al. Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. Biochem. J. 2012; 442: 293-302.
62. Schmucker AC, Wright JB, Cole MD, Brinckerhoff CE. Distal interleukin-1beta (IL-1beta) response element of human matrix metalloproteinase-13 (MMP-13) binds activator protein 1 (AP-1) transcription factors and regulates gene expression. J. Biol. Chem. 2012; 287: 1189-97.
63. Rao BG. Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr. Pharm. Des. 2005; 11: 295-322.
64. Ramnath N, Creaven PJ. Matrix metalloproteinase inhibitors. Curr. Oncol. Rep. 2004; 6: 96-102.
65. Li X, Wu JF. Recent developments in patent anti-cancer agents targeting the matrix metalloproteinases (MMPs). Recent. Pat. Anticancer Drug. Discov. 2010; 5: 109-41.
66. Amour A, Knight CG, Webster A et al. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett. 2000; 473: 275-9.
67. Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 Is a Potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J. Biol. Chem. 2001; 276: 12501-4.
68. Maquoi E, Munaut C, Colige A et al. Stimulation of matrix metalloproteinase-9 expression in human fibrosarcoma cells by synthetic matrix metalloproteinase inhibitors. Exp. Cell Res. 2002; 275: 110-21.
69. Overall CM, Kleifeld O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br. J. Cancer 2006; 94: 941-6.
70. Sparano JA, Bernardo P, Stephenson P et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J. Clin. Oncol. 2004; 22: 4683-90.
71. Moore MJ, Hamm J, Dancey J et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 2003; 21: 3296-302.
72. Nuti E, Tuccinardi T, Rossello A. Matrix metalloproteinase inhibitors: New challenges in the era of post broad-spectrum inhibitors. Curr. Pharm. Des. 2007; 13: 2087-100.
73. Nakabayashi H, Yawata T, Shimizu K. Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells. BMC Cancer. 2010; 10: 339.
74. Mant TG, Bradford D, Amin DM et al. Pharmacokinetics and safety assessments of high-dose and 4-week treatment with S-3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers. Br. J. Clin. Pharmacol. 2007; 63: 512-26.
75. Gooyit M, Lee M, Schroeder VA et al. Selective water-soluble gelatinase inhibitor prodrugs. J. Med. Chem. 2011; 54: 6676-90.
76. Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH. Evolving role of uPA/uPAR system in human cancers. Cancer Treat. Rev. 2008; 34: 122-36.
77. Raghu H, Gondi CS, Dinh DH, Gujrati M, Rao JS. Specific knockdown of uPA/uPAR attenuates invasion in glioblastoma cells and xenografts by inhibition of cleavage and trafficking of Notch -1 receptor. Mol. Cancer 2011; 10: 130.
78. Rao Malla R, Gopinath S, Alapati K, Gorantla B, Gondi CS, Rao JS. Knockdown of cathepsin B and uPAR inhibits CD151 and alpha3beta1 integrin-mediated cell adhesion and invasion in glioma. Mol. Carcinog. 2012. Epub, 11 April 2012; doi:10.1002/mc.21915 (in press).
79. Duriseti S, Goetz DH, Hostetter DR et al. Antagonistic anti-urokinase plasminogen activator receptor (uPAR) antibodies significantly inhibit uPAR-mediated cellular signaling and migration. J. Biol. Chem. 2010; 285: 26878-88.
80. Rabbani SA, Ateeq B, Arakelian A et al. An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo. Neoplasia 2010; 12: 778-88.
81. Ertongur S, Lang S, Wosikowski K, Muehlenweg B, Gires O. Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int. J. Cancer 2004; 110: 815-24.
82. Kobayashi H, Suzuki M, Kanayama N, Nishida T, Takigawa M, Terao T. Suppression of urokinase receptor expression by bikunin is associated with inhibition of upstream targets of extracellular signal-regulated kinase-dependent cascade. Eur. J. Biochem. 2002; 269: 3945-57.
83. Kobayashi H, Suzuki M, Hirashima Y, Terao T. The protease inhibitor bikunin, a novel anti-metastatic agent. Biol. Chem. 2003; 384: 749-54.
84. Barber CG, Dickinson RP, Fish PV. Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-Isoquinolinylguanidines. Bioorg. Med. Chem. Lett. 2004; 14: 3227-30.
85. Rockway TW, Giranda VL. Inhibitors of the proteolytic activity of urokinase type plasminogen activator. Curr. Pharm. Des. 2003; 9: 1483-98.
86. Patarroyo M, Tryggvason K, Virtanen I. Laminin isoforms in tumor invasion, angiogenesis and metastasis. Semin. Cancer Biol. 2002; 12: 197-207.
87. Berno V, Porrini D, Castiglioni F et al. The 67 kDa laminin receptor increases tumor aggressiveness by remodeling laminin-1. Endocr. Relat. Cancer 2005; 12: 393-406.
88. Fülöp T, Larbi A. Putative role of 67 kDa elastin-laminin receptor in tumor invasion. Semin. Cancer Biol. 2002; 12: 219-29.
89. Givant-Horwitz V, Davidson B, Reich R. Laminin-Induced Signaling in Tumor Cells. Cancer Res. 2004; 64: 3572-9.
90. Ardini E, Sporchia B, Pollegioni L et al. Identification of a novel function for 67-kDa laminin receptor: Increase in laminin degradation rate and release of motility fragments. Cancer Res. 2002; 62: 1321-5.
91. Chen J, Alexander JS, Orr AW. Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis. Int. J. Cell. Biol. 2012; 2012: 853703.
92. Lahlou H, Muller WJ. Beta1-integrins signaling and mammary tumor progression in transgenic mouse models: Implications for human breast cancer. Breast Cancer Res. 2011; 13: 229.
93. Lu JG, Li Y, Li L, Kan X. Overexpression of osteopontin and integrin alphav in laryngeal and hypopharyngeal carcinomas associated with differentiation and metastasis. J. Cancer Res. Clin. Oncol. 2011; 137: 1613-8.
94. van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res. 2001; 305: 285-98.
95. Wang P, Ballestrem C, Streuli CH. The C terminus of talin links integrins to cell cycle progression. J. Cell Biol. 2011; 195: 499-513.
96. Shen K, Tolbert CE, Guilluy C et al. The vinculin C-terminal hairpin mediates F-actin bundle formation, focal adhesion, and cell mechanical properties. J. Biol. Chem. 2011; 286: 45103-15.
97. Lawson C, Lim ST, Uryu S, Chen XL, Calderwood DA, Schlaepfer DD. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J. Cell Biol. 2012; 196: 223-32.
98. Parsons SA, Sharma R, Roccamatisi DL et al. Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration. Eur. J. Immunol. 2012; 42: 436-46.
99. Wang Y, Shenouda S, Baranwal S et al. Integrin subunits alpha5 and alpha6 regulate cell cycle by modulating the chk1 and Rb/E2F pathways to affect breast cancer metastasis. Mol. Cancer 2011; 10: 84.
100. Prakash M, Kale S, Ghosh I, Kundu GC, Datta K. Hyaluronan-binding protein 1 (HABP1/p32/gC1qR) induces melanoma cell migration and tumor growth by NF-kappa B dependent MMP-2 activation through integrin alpha(v)beta(3) interaction. Cell. Signal. 2011; 23: 1563-77.
101. Ricart AD, Tolcher AW, Liu G et al. Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 Integrin: A phase I, pharmacokinetic, and biological correlative study. Clin. Cancer Res. 2008; 14: 7924-9.
102. Bell-McGuinn KM, Matthews CM, Ho SN et al. A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol. Oncol. 2011; 121: 273-9.
103. Mulholland DJ, Kobayashi N, Ruscetti M et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 2012; 72: 1878-89.
104. Gately K, Al-Alao B, Dhillon T et al. Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study. Lung Cancer 2012; 75: 217-22.
105. Leystra AA, Deming DA, Zahm CD et al. Mice expressing activated PI3K develop advanced colon cancer. Cancer Res. 2012; 72: 2931-6.
106. Mazure NM, Brahimi-Horn MC, Pouysségur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. Curr. Pharm. Des. 2003; 9: 531-41.
107. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-5.
108. Chen XF, Zhang HJ, Wang HB et al. Transforming growth factor-beta1 induces epithelial-to-mesenchymal transition in human lung cancer cells via PI3K/Akt and MEK/Erk1/2 signaling pathways. Mol. Biol. Rep. 2012; 39: 3549-56.
109. Kattla JJ, Carew RM, Heljic M, Godson C, Brazil DP. Protein kinase B/Akt activity is involved in renal TGF-beta1-driven epithelial-mesenchymal transition in vitro and in vivo. Am. J. Physiol. Renal Physiol. 2008; 295: F215-25.
110. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4- morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 1994; 269: 5241-8.
111. Semba S, Itoh N, Ito M, Harada M, Yamakawa M. The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3′-kinase, in human colon cancer cells. Clin. Cancer Res. 2002; 8: 1957-63.
112. Boehle A, Kurdow R, Boenicke L et al. Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo. Langenbeck's Arch. Surg. 2002; 387: 234-9.
113. Guba M, von Breitenbuch P, Steinbauer M et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat. Med. 2002; 8: 128-35.
114. West KA, Sianna Castillo S, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist. Updat. 2002; 5: 234-48.
115. Chang KY, Tsai SY, Wu CM, Yen CJ, Chuang BF, Chang JY. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin. Cancer Res. 2011; 17: 7116-26.
116. Markman B, Tabernero J, Krop I et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. Oncol. 2012; 3: 399-408.
117. Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T et al. Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Res. 2008; 68: 10187-96.
118. Jones NP, Katan M. Role of phospholipase Cγ1 in Cell spreading requires association with a β-Pix/GIT1-containing complex, leading to activation of Cdc42 and Rac1. Mol. Cell. Biol. 2007; 27: 5790-805.
119. Mouneimne G, Soon L, DesMarais V et al. Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation. J. Cell Biol. 2004; 166: 697-708.
120. Azad N, Iyer AK, Wang L, Liu Y, Lu Y, Rojanasakul Y. Reactive oxygen species-mediated p38 MAPK regulates carbon nanotube-induced fibrogenic and angiogenic responses. Nanotoxicology. 2013; 7: 157-68.
121. Mendoza MC, Er EE, Zhang W et al. ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex. Mol. Cell 2011; 41: 661-71.
122. Donauer J, Schreck I, Liebel U, Weiss C. Role and interaction of p53, BAX and the stress-activated protein kinases p38 and JNK in benzo(a)pyrene-diolepoxide induced apoptosis in human colon carcinoma cells. Arch. Toxicol. 2012; 86: 329-37.
123. Kang DW, Park MH, Lee YJ et al. Phorbol ester up-regulates phospholipase D1 but not phospholipase D2 expression through a PKC/Ras/ERK/NFkappaB-dependent pathway and enhances matrix metalloproteinase-9 secretion in colon cancer cells. J. Biol. Chem. 2008; 283: 4094-104.
124. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 2002; 4: E131-6.
125. Park S, Jung HH, Park YH, Ahn JS, Im YH. ERK/MAPK pathways play critical roles in EGFR ligands-induced MMP1 expression. Biochem. Biophys. Res. Commun. 2011; 407: 680-6.
126. Yoshizuka N, Chen RM, Xu Z et al. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol. Cell. Biol. 2012; 32: 606-18.
127. Komers R, Oyama TT, Beard DR et al. Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats. Br. J. Pharmacol. 2011; 162: 163-74.
128. Amano M, Nakayama M, Kaibuchi K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton (Hoboken) 2010; 67: 545-54.
129. Nakajima M, Hayashi K, Katayama Ki et al. WF-536 prevents tumor metastasis by inhibiting both tumor motility and angiogenic actions. Eur. J. Pharm. 2003; 459: 113-20.
130. Holt SV, Logie A, Odedra R et al. The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br. J. Cancer 2012; 106: 858-66.
131. Haagensen EJ, Kyle S, Beale GS, Maxwell RJ, Newell DR. The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br. J. Cancer 2012; 106: 1386-94.
132. Summy JM, Trevino JG, Baker CH, Gallick GE. c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK. Pancreas 2005; 31: 263-74.
133. Beierle EA, Ma X, Trujillo A, Kurenova EV, Cance WG, Golubovskaya VM. Inhibition of focal adhesion kinase and src increases detachment and apoptosis in human neuroblastoma cell lines. Mol. Carcinog. 2010; 49: 224-34.
134. Herold CI, Chadaram V, Peterson BL et al. Phase II trial of dasatinib in patients with metastatic breast cancer using real-time pharmacodynamic tissue biomarkers of Src inhibition to escalate dosing. Clin. Cancer Res. 2011; 17: 6061-70.
135. Bendinelli P, Maroni P, Matteucci E, Desiderio MA. Comparative role of acetylation along c-SRC/ETS1 signaling pathway in bone metastatic and invasive mammary cell phenotypes. Biochim. Biophys. Acta 2011; 1813: 1767-76.
136. Sen B, Johnson FM. Regulation of SRC family kinases in human cancers. J. Signal Transduct. 2011; 2011: 865819.
137. Schenone S, Brullo C, Musumeci F, Botta M. Novel dual Src/Abl inhibitors for hematologic and solid malignancies. Expert Opin. Investig. Drugs 2010; 19: 931-45.
138. Keller G, Schafhausen P, Brummendorf TH. Bosutinib: A dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia. Expert. Rev. Hematol. 2009; 2: 489-97.
139. Lara PN Jr, Longmate J, Evans CP et al. A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: A California Cancer Consortium study. Anticancer Drugs 2009; 20: 179-84.
140. Aplenc R, Blaney SM, Strauss LC et al. Pediatric phase I trial and pharmacokinetic study of dasatinib: A report from the children's oncology group phase I consortium. J. Clin. Oncol. 2011; 29: 839-44.
141. Trask PC, Cella D, Besson N, Kelly V, Masszi Ts, Kim D-W. Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia. Leuk. Res. 2012; 36: 438-42.
142. Khoury HJ, Cortes JE, Kantarjian HM et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119: 3403-12.
143. Campone M, Bondarenko I, Brincat S et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann. Oncol. 2012; 23: 610-7.
144. Gucalp A, Sparano JA, Caravelli J et al. Phase II Trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin. Breast Cancer. 2011; 11: 306-11.
145. Fury MG, Baxi S, Shen R et al. Phase II Study of Saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Anticancer Res. 2011; 31: 249-53.
146. Renouf D, Moore M, Hedley D et al. A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. Invest. New Drugs 2012; 30: 779-86.
147. Fujisaka Y, Onozawa Y, Kurata T et al. First report of the safety, tolerability, and pharmacokinetics of the Src kinase inhibitor saracatinib (AZD0530) in Japanese patients with advanced solid tumours. Invest. New Drugs. 2013; 31: 108-14.
148. Herbolsheimer P, Kapoor R, Smith K et al. Phase I trial of dasatinib and ixabepilone in patients with solid tumors. Invest. New Drugs. 2013; 31: 92-8.
149. Kantarjian HM, Shah NP, Cortes JE et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 1123-9.
150. Banerji U. Heat shock protein 90 as a drug target: Some like it hot. Clin. Cancer Res. 2009; 15: 9-14.
151. Neckers L. Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr. Top. Med. Chem. 2006; 6: 1163-71.
152. Powers MV, Workman P. Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr. Relat. Cancer 2006; 13: S125-35.
153. Stravopodis DJ, Margaritis LH, Voutsinas GE. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr. Med. Chem. 2007; 14: 3122-38.
154. Modi S, Stopeck A, Linden H et al. HSP90 inhibition is effective in breast cancer: A phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin. Cancer Res. 2011; 17: 5132-9.
155. Messaoudi S, Peyrat JF, Brion JD, Alami M. Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med. Chem. 2008; 8: 761-82.