期刊
MOLECULAR ONCOLOGY
卷 6, 期 5, 页码 530-541出版社
WILEY
DOI: 10.1016/j.molonc.2012.06.006
关键词
Sunitinib; Bortezomib; NF kappa B; Synergy; Endometrial carcinoma
类别
资金
- Grupos Estables de la Asociacion Contra el Cancer
- Fundacio Cientifica AECC, Catalunya contra el Cancer, Lleida
- Ministerio de Educacion y Ciencia (Programa Juan de la Cierva)
- Fundacio Alicia Cuello de Merigo
- [FIS 2010 PI100922]
- [FIS 2006 PI060832]
- [RD06/0020/1034]
- [2009 SGR 794]
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 NF kappa B transcriptional activity either at basal level or activation by EGF or TNF-alpha. We observed that Sunitinib was able to inhibit the Bortezomib-induced NF kappa B transcriptional activity which correlates with a decrease of the phosphorylated levels of IKK alpha and beta, p65 and I kappa B alpha. 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. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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