Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-κB

The transcription factor nuclear factor-kappa B (NF-kappa B) has been shown to be constitutively activated in various human malignancies, including leukemia, lymphoma and a number of solid tumors. NF-kappa B regulates the transcriptional of genes important for tumor invasion, metastasis and chemoresistance. The sesquiterpene lactone parthenolide, an inhibition of NF-kappa B, has been used conventionally to treat migraines and inflammation. In this study, renal cancer cell lines OUR-10 and ACHN were used for in vitro experiments to evaluate growth- inhibitory effects of parthenolide. An OUR-10 xenograft model in nude mice was also used to investigate the in vivo growth-inhibitory effects of parthenolide. Apoptosis in response to treatment of OUR-10 cells with parthenolide was confirmed. Localization of NF-kappa B in response to parthenolide treatment was examined of by immunofluorostaining of OUR-10 cells with antibody against NF-kappa B p65 and by Western blot analysis of OUR-10 cell and tumor nuclear and cytosol fraction. Parthenolide effectively inhibited proliferation of cultured OUR-10 cells and triggered apoptosis in vitro. Subcutaneous injection or oral administration of parthenolide showed significant tumor growth inhibition in the xenograft model via decreased production of interleukin-8 (IL-8) or vascular endothelial growth factor (VEGF). Immunohistochemistry and Western blot analysis showed decreased nuclear localization of NF-kappa B and phosphorylated NF-kappa B protein and subsequently expression of MMP-9, Bcl-xL and Cox-2 in response to parthenolide treatment. These results indicate that parthenolide is a useful in the treatment of renal cell carcinoma and acts via inhibition of NF-kappa B. (c) 2007 Wiley-Liss. Inc.