The Rac inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse model

Translational Oncology

Volumn 7, Issue 5, 2014, Pages 546-555

  Castillo Pichardo, Linette ^a,b   Humphries Bickley, Tessa ^a   De La Parra, Columba ^a   Forestier Roman, Ingrid ^c   Martinez Ferrer, Magaly ^c   Hernandez, Eliud ^c   Vlaar, Cornelis ^c   Ferrer Acosta, Yancy ^d   Washington, Anthony V ^d   Cubano, Luis A ^b   Rodriguez Orengo, Jose ^a   Dharmawardhane, Suranganie ^a  

^a UNIVERSITY OF PUERTO RICO SCHOOL OF MEDICINE   (Puerto Rico)

^b Universidad Central del Caribe School of Medicine   (Puerto Rico)

^c UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS   (Puerto Rico)

^d UNIVERSITY OF PUERTO RICO   (Puerto Rico)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CASPASE 3; CASPASE 7; CELL SURFACE RECEPTOR; CYCLIN D; EHOP 016; P21 ACTIVATED KINASE; PROTEIN CDC42; PROTEIN KINASE B; UNCLASSIFIED DRUG;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS ASSAY; ARTICLE; BREAST TUMOR; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CELL VIABILITY; CONTROLLED STUDY; FEMALE; FLUORESCENCE IMAGING; HUMAN; HUMAN CELL; IC50; IMMUNOHISTOCHEMISTRY; MASS SPECTROMETRY; METASTASIS; MOUSE; NONHUMAN; ONCOGENE C MYC; SIGNAL TRANSDUCTION; TUMOR GROWTH; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY; WESTERN BLOTTING;

EID: 84915798379     PISSN: None     EISSN: 19365233     Source Type: Journal    
DOI: 10.1016/j.tranon.2014.07.004     Document Type: Article

References (72)

1. Condeelis J, Singer RH, and Segall JE (2005). The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol 21, 695–718.
2. Steeg PS (2003). Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer 3, 55–63.
3. Pai SY, Kim C, and Williams DA (2010). Rac GTPases in human diseases. Dis Markers 29, 177–187.
4. Ridley AJ (2006). Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16, 522–529.
5. Hall A (2005). Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33, 891–895.
6. Azios NG, Krishnamoorthy L, Harris M, Cubano LA, Cammer M, and Dharmawardhane SF (2007). Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. Neoplasia 9, 147–158.
7. Baugher PJ, Krishnamoorthy L, Price JE, and Dharmawardhane SF (2005). Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res 7, R965-974.
8. Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, and Symons M (2005). Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene 24, 7821–7829.
9. Mira JP, Benard V, Groffen J, Sanders LC, and Knaus UG (2000). Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci U S A 97, 185–189.
10. Yoshida T, Zhang Y, Rivera Rosado LA, Chen J, Khan T, Moon SY, and Zhang B (2010). Blockade of Rac1 activity induces G1 cell cycle arrest or apoptosis in breast cancer cells through downregulation of cyclin D1, survivin, and X-linked inhibitor of apoptosis protein. Mol Cancer Ther 9, 1657–1668.
11. Qiu RG, Chen J, Kirn D, McCormick F, and Symons M (1995). An essential role for Rac in Ras transformation. Nature 374, 457–459.
12. Wang Z, Pedersen E, Basse A, Lefever T, Peyrollier K, Kapoor S, Mei Q, Karlsson R, Chrostek-Grashoff A, and Brakebusch C (2010). Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation In Vivo. Oncogene 29, 3362–3373.
13. Whale A, Hashim FN, Fram S, Jones GE, and Wells CM (2011). Signalling to cancer cell invasion through PAK family kinases. Front Biosci 16, 849–864.
14. Yang HW, Shin MG, Lee S, Kim JR, Park WS, Cho KH, Meyer T, and DoHW (2012). Cooperative activation of PI3K by Ras and Rho family small GTPases. Mol Cell 47, 281–290.
15. Wertheimer E, Gutierrez-Uzquiza A, Rosemblit C, Lopez-Haber C, Soledad SM, and Kazanietz MG (2012). Rac signaling in breast cancer: A tale of GEFs and GAPs. Cell Signal 24, 353–362.
16. Menges CW, Sementino E, Talarchek J, Xu J, Chernoff J, Peterson JR, and Testa JR (2012). Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways. Mol Cancer Res 10, 1178–1188.
17. Katz E, Sims AH, Sproul D, Caldwell H, Dixon MJ, Meehan RR, and Harrison DJ (2012). Targeting of Rac GTPases blocks the spread of intact human breast cancer. Oncotarget 3, 608–619.
18. Saci A, Cantley LC, and Carpenter CL (2011). Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell 42, 50–61.
19. Boettner B and Van Aelst L (2002). The role of Rho GTPases in disease development. Gene 286, 155–174 [JID - 7706761].
20. Mack NA, Whalley HJ, Castillo-Lluva S, and Malliri A (2011). The diverse roles of Rac signaling in tumorigenesis. Cell Cycle 10, 1571–1581.
21. Vigil D, Cherfils J, Rossman KL, and Der CJ (2010). Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat RevCancer 10, 842–857.
22. Cook DR, Rossman KL, and Der CJ (2014). Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease. Oncogene 33, 4021–4035.
23. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, and Choi M, et al (2012). Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44, 1006–1014.
24. Singh A, Karnoub AE, Palmby TR, Lengyel E, Sondek J, and Der CJ (2004). Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 23, 9369–9380.
25. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, and Lengyel E (2000). Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19, 3013–3020.
26. Stengel K and Zheng Y (2011). Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal 23, 1415–1423.
27. Rossman KL, Der CJ, and Sondek J (2005). GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6, 167–180.
28. Schmidt A and Hall A (2002). Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 16, 1587–1609.
29. Bernards A (2003). GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta 1603, 47–82.
30. Adams III HC, Chen R, Liu Z, and Whitehead IP (2010). Regulation of breast cancer cell motility by T-cell lymphoma invasion and metastasis-inducing protein. Breast Cancer Res 12, R69-83.
31. Palmby TR, Abe K, Karnoub AE, and Der CJ (2004). Vav transformation requires activation of multiple GTPases and regulation of gene expression. Mol Cancer Res 2, 702–711.
32. Miller SL, DeMaria JE, Freier DO, Riegel AM, and Clevenger CV (2005). Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Mol Endocrinol 19, 939–949.
33. Minard ME, Kim LS, Price JE, and Gallick GE (2004). The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat 84, 21–32.
34. Sosa MS, Lopez-Haber C, Yang C, Wang H, Lemmon MA, Busillo JM, Luo J, Benovic JL, Klein-Szanto A, and Yagi H, et al (2010). Identification of the Rac- GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol Cell 40, 877–892.
35. Montero JC, Seoane S, Ocana A, and Pandiella A (2011). P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer. Oncogene 30, 1059–1071.
36. Gao Y, Dickerson JB, Guo F, Zheng J, and Zheng Y (2004). Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101, 7618–7623.
37. Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, Perrotti D, Neviani P, Druker BJ, Setchell KD, and Zheng Y, et al (2007). Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCRABL- induced myeloproliferative disease. Cancer Cell 12, 467–478.
38. Binker MG, Binker-Cosen AA, Gaisano HY, and Cosen-Binker LI (2008). Inhibition of Rac1 decreases the severity of pancreatitis and pancreatitisassociated lung injury in mice. Exp Physiol 93, 1091–1103.
39. Gastonguay A, Berg T, Hauser AD, Schuld N, Lorimer E, and Williams CL (2012). The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer Biol Ther 13, 647–656.
40. Mizukawa B, Wei J, Shrestha M, Wunderlich M, Chou FS, Griesinger A, Harris CE, Kumar AR, Zheng Y, and Williams DA, et al (2011). Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia. Blood 118, 5235–5245.
41. Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, Wu YQ, Song J, Yan J, and Wu LJ (2011). Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. Int J Mol Med 28, 769–776.
42. Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B, and Fritz G (2011). Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors. PLoS One 6, e26413–e26423.
43. Zhao Y, Wang Z, Jiang Y, and Yang C (2011). Inactivation of Rac1 reduces Trastuzumab resistance in PTEN deficient and insulin-like growth factor I receptor overexpressing human breast cancer SKBR3 cells. Cancer Lett 313, 54–63.
44. Ferri N, Corsini A, Bottino P, Clerici F, and Contini A (2009). Virtual screening approach for the identification of new Rac1 inhibitors. J Med Chem 52, 4087–4090.
45. Shutes A, Onesto C, Picard V, Leblond B, Schweighoffer F, and Der CJ (2007). Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases. J Biol Chem 282, 35666–35678.
46. Zins K, Lucas T, Reichl P, Abraham D, and Aharinejad S (2013). A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice. PLoS One 8, e74924–e74936.
47. Cardama GA, Comin MJ, Hornos L, Gonzalez N, Defelipe L, Turjanski AG, Alonso DF, Gomez DE, and Menna LP (2013). Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med Chem 14, 840–851.
48. Zins K, Gunawardhana S, Lucas T, Abraham D, and Aharinejad S (2013). Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity. J Transl Med 11, 295–310.
49. Surviladze Z, Waller A, Strouse JJ, Bologa C, Ursu O, Salas V, Parkinson JF, Phillips GK, Romero E, and Wandinger-Ness A, et al (2010). A potent and selective inhibitor of Cdc42 GTPase. Anonymous; 2010.
50. Maes H, Van ES, Krysko DV, Vandenabeele P, Nys K, Rillaerts K, Garg AD, Verfaillie T, andAgostinis P (2014). BNIP3 supportsmelanoma cellmigration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell Death Dis 5, e1127–e1138.
51. Hernandez E, De LM-P, Dharmawardhane S, and Vlaar CP (2010). Novel inhibitors of Rac1 in metastatic breast cancer. P R Health Sci J 29, 348–356.
52. Montalvo-Ortiz BL, Castillo-Pichardo L, Hernandez E, Humphries-Bickley T, De LM-P, Cubano LA, Vlaar CP, and Dharmawardhane S (2012). Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem 287, 13228–13238.
53. Martin H, Mali RS, Ma P, Chatterjee A, Ramdas B, Sims E, Munugalavadla V, Ghosh J, Mattingly RR, and Visconte V, et al (2013). Pak and Rac GTPases promote oncogenic KIT-induced neoplasms. J Clin Invest 123, 4449–4463.
54. Manes TD and Pober JS (2013). TCR-driven transendothelial migration of human effector memory CD4 T cells involves Vav, Rac, and myosin IIA. J Immunol 190, 3079–3088.
55. Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, and Dharmawardhane SF (2008). Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1, 19–27.
56. Kong W, He L, Coppola M, Guo J, Esposito NN, Coppola D, and Cheng JQ (2010). MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem 285, 17869–17879.
57. Castillo-Pichardo L, Martinez-Montemayor MM, Martinez JE, Wall KM, Cubano LA, and Dharmawardhane S (2009). Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols. Clin Exp Metastasis 26, 505–516.
58. Yang M, Baranov E, Jiang P, Sun FX, Li XM, Li L, Hasegawa S, Bouvet M, Al- Tuwaijri M, and Chishima T, et al (2000). Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci U S A 97, 1206–1211.
59. Vega FM and Ridley AJ (2008). Rho GTPases in cancer cell biology. FEBS Lett 582, 2093–2101.
60. Chan SK, Hill ME, and Gullick WJ (2006). The role of the epidermal growth factor receptor in breast cancer. J Mammary Gland Biol Neoplasia 11, 3–11.
61. Arteaga CL and Truica CI (2004). Challenges in the development of anti-epidermal growth factor receptor therapies in breast cancer. Semin Oncol 31, 3–8.
62. King H, Nicholas NS, and Wells CM (2014). Role of p-21-activated kinases in cancer progression. Int Rev Cell Mol Biol 309, 347–387.
63. Galan Moya EM, Le GA, and Gavard J (2009). PAKing up to the endothelium. Cell Signal 21, 1727–1737.
64. Sandri C, Caccavari F, Valdembri D, Camillo C, Veltel S, Santambrogio M, Lanzetti L, Bussolino F, Ivaska J, and Serini G (2012). The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell Res 22, 1479–1501.
65. Van Buul JD, Geerts D, and Huveneers S (2014). Rho GAPs and GEFs: Controling switches in endothelial cell adhesion. Cell Adh Migr 8, 108–124.
66. Turner M and Billadeau DD (2002). VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol 2, 476–486.
67. Valderrama F, Thevapala S, and Ridley AJ (2012). Radixin regulates cell migration and cell-cell adhesion through Rac1. J Cell Sci 125, 3310–3319.
68. Boureux A, Furstoss O, Simon V, and Roche S (2005). Abl tyrosine kinase regulates a Rac/JNK and a Rac/Nox pathway for DNA synthesis and Myc expression induced by growth factors. J Cell Sci 118, 3717–3726.
69. Fournier AK, Campbell LE, Castagnino P, Liu WF, Chung BM, Weaver VM, Chen CS, and Assoian RK (2008). Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion. J Cell Sci 121, 226–233.
70. Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, Ross FP, and Zhao H (2010). Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Invest 120, 1981–1993.
71. Zhang Y, Rivera Rosado LA, Moon SY, and Zhang B (2009). Silencing of D4-GDI inhibits growth and invasive behavior in MDA-MB-231 cells by activation of Rac-dependent p38 and JNK signaling. J Biol Chem 284, 12956–12965.
72. Yang FC, Kapur R, King AJ, Tao W, Kim C, Borneo J, Breese R, Marshall M, Dinauer MC, and Williams DA (2000). Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity 12, 557–568.