title: Combination of Vorinostat and caspase-8 inhibition exhibits high anti-tumoral activity on endometrial cancer cells.
abstract: Histone deacetylase inhibitors such as Vorinostat display anti-neoplastic activity against a variety of solid tumors. Here, we have investigated the anti-tumoral activity of Vorinostat on endometrial cancer cells. We have found that Vorinostat caused cell growth arrest, loss of clonogenic growth and apoptosis of endometrial cancer cells. Vorinostat-induced the activation of caspase-8 and -9, the initiators caspases of the extrinsic and the intrinsic apoptotic pathways, respectively. Next, we investigated the role of the extrinsic pathway in apoptosis triggered by Vorinostat. We found that Vorinostat caused a dramatic decrease of FLIP mRNA and protein levels. However, overexpression of the long from of FLIP did not block Vorinostat-induced apoptosis. To further investigate the role of extrinsic apoptotic pathway in Vorinostat-induced apoptosis, we performed an shRNA-mediated knock-down of caspase-8. Surprisingly, downregulation of caspase-8 alone caused a marked decrease in clonogenic ability and reduced the growth of endometrial cancer xenografts in vivo, revealing that targeting caspase-8 may be an attractive target for anticancer therapy on endometrial tumors. Furthermore, combination of caspase-8 inhibition and Vorinostat treatment caused an enhancement of apoptotic cell death and a further decrease of clonogenic growth of endometrial cancer cells. More importantly, combination of Vorinostat and caspase-8 inhibition caused a nearly complete inhibition of tumor xenograft growth. Finally, we demonstrate that cell death triggered by Vorinostat alone or in combination with caspase-8 shRNAs was inhibited by the anti-apoptotic protein Bcl-XL. Our results suggest that combinatory therapies using Vorinostat treatment and caspase-8 inhibition can be an effective treatment for endometrial carcinomas.
authors.affiliation: Departamento de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, Lleida, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Bergadà
authors.forename: Annabel
authors.initials: A
authors.lastname: Sorolla
authors.forename: Andree
authors.initials: A
authors.lastname: Yeramian
authors.forename: Nuria
authors.initials: N
authors.lastname: Eritja
authors.forename: Cristina
authors.initials: C
authors.lastname: Mirantes
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D000077337:Vorinostat; D053181:Caspase 8
keywords: Caspase-8; Endometrial cancer; Histone deacetylase inhibitors; Vorinostat