title: Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells.
abstract: Endometrial carcinoma is one of the most common malignancies in the female genital tract, usually treated by surgery and radiotherapy. Chemotherapy is used when endometrial carcinoma is associated with widespread metastasis or when the tumor recurs after radiation therapy. In the present study, we demonstrate that the tyrosine kinase receptor inhibitor Sunitinib reduces cell viability, proliferation, clonogenicity and induces apoptotic cell death in endometrial carcinoma cell lines, which is not due to its action through the most known targets like VEGFR, nor through EGFR as demonstrated in this work. Interestingly, Sunitinib reduces NFκB transcriptional activity either at basal level or activation by EGF or TNF-α. We observed that Sunitinib was able to inhibit the Bortezomib-induced NFκB transcriptional activity which correlates with a decrease of the phosphorylated levels of IKKα and β, p65 and IκBα. We evaluated the nature of the interaction between Sunitinib and Bortezomib by the dose effect method and identified a synergistic effect (combination index < 1). Analogously, silencing of p65 expression by lentiviral-mediated short-hairpin RNA delivery in Bortezomib treated cells leads to a strongly increased sensitivity to Bortezomib apoptotic cell death. Altogether our results suggest that the combination of Sunitinib and Bortezomib could be considered a promising treatment for endometrial carcinoma after failure of surgery and radiation.
authors: Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRB-Lleida, 25198 Lleida, Spain.
authors: Anabel
authors: A
authors: Sorolla
authors: Andrée
authors: A
authors: Yeramian
authors: Joan
authors: J
authors: Valls
authors: Xavier
authors: X
authors: Dolcet
authors: Laura
authors: L
authors: Bergadà
authors: Antoni
authors: A
authors: Llombart-Cussac
authors: Rosa Maria
authors: RM
authors: Martí
authors: Xavier
authors: X
authors: Matias-Guiu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007211:Indoles; D016328:NF-kappa B; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; D000077210:Sunitinib