Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation

Oncotarget

Volumn 7, Issue 22, 2016, Pages 32200-32209

  Coleman, David T ^a   Gray, Alana L ^a   Stephens, Charles A ^a   Scott, Matthew L ^a   Cardelli, James A ^a  

^a LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

Cancer associated fibroblast; Cardiac glycosides; Digoxin; Drug screen; Tumor microenvironment

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); DIGOXIN; FIBRONECTIN; SMAD PROTEIN; TRANSFORMING GROWTH FACTOR BETA; ANTINEOPLASTIC AGENT; CARDIAC GLYCOSIDE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CALCIUM SIGNALING; CANCER THERAPY; CELL DEATH; CELL DIFFERENTIATION; CELL VIABILITY; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; DRUG REPOSITIONING; DRUG SCREENING; ENZYME INHIBITION; EXTRACELLULAR MATRIX; FETUS; FIBROBLAST; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOFLUORESCENCE TEST; PROTEIN EXPRESSION; PROTEIN FUNCTION; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; TUMOR MICROENVIRONMENT; WESTERN BLOTTING; ANTAGONISTS AND INHIBITORS; CANCER ASSOCIATED FIBROBLAST; CELL SHAPE; CELL SURVIVAL; DOSE RESPONSE; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETIC TRANSFECTION; GENETICS; MALE; METABOLISM; MOLECULAR LIBRARY; MYOFIBROBLAST; PATHOLOGY; PROMOTER REGION; PROSTATE TUMOR; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; CALCIUM SIGNALING; CANCER-ASSOCIATED FIBROBLASTS; CARDIAC GLYCOSIDES; CELL DIFFERENTIATION; CELL LINE, TUMOR; CELL SHAPE; CELL SURVIVAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG REPOSITIONING; FIBRONECTINS; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MALE; MYOFIBROBLASTS; PROMOTER REGIONS, GENETIC; PROSTATIC NEOPLASMS; SMAD PROTEINS; SMALL MOLECULE LIBRARIES; SODIUM-POTASSIUM-EXCHANGING ATPASE; TRANSFECTION; TRANSFORMING GROWTH FACTOR BETA; TUMOR MICROENVIRONMENT;

EID: 84973575250     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.8609     Document Type: Article

References (56)

1. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006; 6:392-401.
2. Rosenbloom J, Castro SV, Jimenez SA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. 2010; 152:159-166.
3. Polanska UM, Orimo A. Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol. 2013; 228:1651-1657.
4. Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol. 2007; 257:143-179.
5. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010; 70:6945-6956.
6. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996; 76:69-125.
7. Allen M, Louise Jones J. Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol. 2011; 223:162-176.
8. Slany A, Bileck A, Muqaku B, Gerner C. Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy. Breast. 2015; 24:532-538.
9. Ayala G, Tuxhorn JA, Wheeler TM, Frolov A, Scardino PT, Ohori M, Wheeler M, Spitler J, Rowley DR. Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin Cancer Res. 2003; 9:4792-4801.
10. Chen JL, Espinosa I, Lin AY, Liao OY, van de Rijn M, West RB. Stromal responses among common carcinomas correlated with clinicopathologic features. Clin Cancer Res. 2013; 19:5127-5135.
11. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, Richardson A, Weinberg RA. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A. 2004; 101:4966-4971.
12. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005; 121:335-348.
13. Dimanche-Boitrel MT, Vakaet L, Jr., Pujuguet P, Chauffert B, Martin MS, Hammann A, Van Roy F, Mareel M, Martin F. In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of tumor-associated myofibroblasts. Int J Cancer. 1994; 56:512-521.
14. Lewis MP, Lygoe KA, Nystrom ML, Anderson WP, Speight PM, Marshall JF, Thomas GJ. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer. 2004; 90:822-832.
15. Siegel PM, Massague J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003; 3:807-821.
16. Busch S, Acar A, Magnusson Y, Gregersson P, Ryden L, Landberg G. TGF-beta receptor type-2 expression in cancerassociated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer. Oncogene. 2015; 34:27-38.
17. Ronnov-Jessen L, Petersen OW. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest. 1993; 68:696-707.
18. Hawinkels LJ, Paauwe M, Verspaget HW, Wiercinska E, van der Zon JM, van der Ploeg K, Koelink PJ, Lindeman JH, Mesker W, ten Dijke P, Sier CF. Interaction with colon cancer cells hyperactivates TGF-beta signaling in cancerassociated fibroblasts. Oncogene. 2014; 33:97-107.
19. Ting HJ, Deep G, Jain AK, Cimic A, Sirintrapun J, Romero LM, Cramer SD, Agarwal C, Agarwal R. Silibinin prevents prostate cancer cell-mediated differentiation of naive fibroblasts into cancer-associated fibroblast phenotype by targeting TGF beta2. Mol Carcinog. 2015; 54:730-741.
20. Macias MJ, Martin-Malpartida P, Massague J. Structural determinants of Smad function in TGF-beta signaling. Trends Biochem Sci. 2015; 40:296-308.
21. Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-beta, WNT, and YAP/TAZ converge. Front Med (Lausanne). 2015; 2:59.
22. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25:719-734.
23. Blagosklonny MV. A new science-business paradigm in anticancer drug development. Trends Biotechnol. 2003; 21:103-106.
24. Peiris-Pages M, Sotgia F, Lisanti MP. Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose. Oncoscience. 2015; 2:696-699.
25. Jeong da E, Song HJ, Lim S, Lee SJ, Lim JE, Nam DH, Joo KM, Jeong BC, Jeon SS, Choi HY, Lee HW. Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. Oncotarget. 2015; 6:33046-33064. doi: 10.18632/oncotarget.5422.
26. Chang WL, Hsu LC, Leu WJ, Chen CS, Guh JH. Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer: a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation. Oncotarget. 2015; 6:39806-39820. doi: 10.18632/oncotarget.5655.
27. Triscott J, Lee C, Hu K, Fotovati A, Berns R, Pambid M, Luk M, Kast RE, Kong E, Toyota E, Yip S, Toyota B, Dunn SE. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget. 2012; 3:1112-1123. doi: 10.18632/oncotarget.604.
28. Kast RE, Boockvar JA, Bruning A, Cappello F, Chang WW, Cvek B, Dou QP, Duenas-Gonzalez A, Efferth T, Focosi D, Ghaffari SH, Karpel-Massler G, Ketola K, et al. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget. 2013; 4:502-530. doi: 10.18632/oncotarget.969.
29. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006; 113:2556-2564.
30. Webber MM, Trakul N, Thraves PS, Bello-DeOcampo D, Chu WW, Storto PD, Huard TK, Rhim JS, Williams DE. A human prostatic stromal myofibroblast cell line WPMY- 1: a model for stromal-epithelial interactions in prostatic neoplasia. Carcinogenesis. 1999; 20:1185-1192.
31. Jacobs JP, Jones CM, Baille JP. Characteristics of a human diploid cell designated MRC-5. Nature. 1970; 227:168-170.
32. Schauer IG, Ressler SJ, Tuxhorn JA, Dang TD, Rowley DR. Elevated epithelial expression of interleukin-8 correlates with myofibroblast reactive stroma in benign prostatic hyperplasia. Urology. 2008; 72:205-213.
33. Bhattacharyya S, Chen SJ, Wu M, Warner-Blankenship M, Ning H, Lakos G, Mori Y, Chang E, Nihijima C, Takehara K, Feghali-Bostwick C, Varga J. Smad-independent transforming growth factor-beta regulation of early growth response-1 and sustained expression in fibrosis: implications for scleroderma. Am J Pathol. 2008; 173:1085-1099.
34. Chen SJ, Ning H, Ishida W, Sodin-Semrl S, Takagawa S, Mori Y, Varga J. The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression. J Biol Chem. 2006; 281:21183-21197.
35. Crambert G, Schaer D, Roy S, Geering K. New Molecular Determinants Controlling the Accessibility of Ouabain to Its Binding Site in Human Na,K-ATPase a Isoforms. Molecular Pharmacology. 2004; 65:335-341.
36. Ritchie MF, Zhou Y, Soboloff J. Transcriptional mechanisms regulating Ca(2+) homeostasis. Cell Calcium. 2011; 49:314-321.
37. Wicks SJ, Lui S, Abdel-Wahab N, Mason RM, Chantry A. Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol Cell Biol. 2000; 20:8103-8111.
38. Ming M, Manzini I, Le W, Krieglstein K, Spittau B. Thapsigargin-induced Ca2+ increase inhibits TGFbeta1- mediated Smad2 transcriptional responses via Ca2+/ calmodulin-dependent protein kinase II. J Cell Biochem. 2010; 111:1222-1230.
39. Strell C, Rundqvist H, Ostman A. Fibroblasts-a key host cell type in tumor initiation, progression, and metastasis. Ups J Med Sci. 2012; 117:187-195.
40. Hanley CJ, Noble F, Ward M, Bullock M, Drifka C, Mellone M, Manousopoulou A, Johnston HE, Hayden A, Thirdborough S, Liu Y, Smith DM, Mellows T, et al. A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers. Oncotarget. 2015; doi: 10.18632/oncotarget.6740.
41. Akiyama SK, Olden K, Yamada KM. Fibronectin and integrins in invasion and metastasis. Cancer Metastasis Rev. 1995; 14:173-189.
42. Ruoslahti E. Fibronectin in cell adhesion and invasion. Cancer Metastasis Rev. 1984; 3:43-51.
43. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, Friedl A, Keely PJ. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011; 178:1221-1232.
44. Thant AA, Nawa A, Kikkawa F, Ichigotani Y, Zhang Y, Sein TT, Amin AR, Hamaguchi M. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin Exp Metastasis. 2000; 18:423-428.
45. Lowy CM, Oskarsson T. Tenascin C in metastasis: A view from the invasive front. Cell Adh Migr. 2015; 9:112-124.
46. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001; 12:2730-2741.
47. Wang RF, Zhang LH, Shan LH, Sun WG, Chai CC, Wu HM, Ibla JC, Wang LF, Liu JR. Effects of the fibroblast activation protein on the invasion and migration of gastric cancer. Exp Mol Pathol. 2013; 95:350-356.
48. Teichgraber V, Monasterio C, Chaitanya K, Boger R, Gordon K, Dieterle T, Jager D, Bauer S. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. Adv Med Sci. 2015; 60:264-272.
49. Peyton SR, Ghajar CM, Khatiwala CB, Putnam AJ. The emergence of ECM mechanics and cytoskeletal tension as important regulators of cell function. Cell Biochem Biophys. 2007; 47:300-320.
50. Wei SC, Yang J. Forcing through tumor metastasis: The interplay between tissue rigidity and epithelialmesenchymal transition. Trends Cell Biol. 2015; doi: 10.1016/j.tcb.2015.09.009.
51. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G, Sahai E. Mechanotransduction and YAPdependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013; 15:637-646.
52. Miles FL, Sikes RA. Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res. 2014; 12:297-312.
53. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013; 31:2205-2218.
54. Ambrosy AP, Butler J, Ahmed A, Vaduganathan M, van Veldhuisen DJ, Colucci WS, Gheorghiade M. The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol. 2014; 63:1823-1832.
55. La J, Reed EB, Koltsova SV, Akimova O, Hamanaka RB, Mutlu GM, Orlov SN, Dulin NO. Regulation of myofibroblast differentiation by cardiac glycosides. Am J Physiol Lung Cell Mol Physiol. 2016:ajplung.00322.02015.
56. Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, Divgi CR, Hanson LH, Mitchell P, Gansen DN, Larson SM, Ingle JN, Hoffman EW, et al. A Phase I doseescalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003; 9:1639-1647.