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

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to be constitutively activated in various human malignancies, including leukemia, lymphoma and a number of solid tumors. NF-kappaB regulates the transcriptional of genes important for tumor invasion, metastasis and chemoresistance. The sesquiterpene lactone parthenolide, an inhibition of NF-kappaB, 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-kappaB in response to parthenolide treatment was examined of by immunofluorostaining of OUR-10 cells with antibody against NF-kappaB 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-kappaB and phosphorylated NF-kappaB 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-kappaB.

• Authors: Daizo Oka, Kazuo Nishimura, Masahiro Shiba, Yasutomo Nakai, Yasuyuki Arai, Masashi Nakayama, Hitoshi Takayama, Hitoshi Inoue, Akihiko Okuyama, Norio Nonomura
• Journal: International journal of cancer (Int J Cancer) Vol. 120 Issue 12 Pg. 2576-81 (Jun 15 2007) ISSN: 0020-7136 [Print] United States
• PMID: 17290398 (Publication Type: Journal Article)

Chemical References

• Interleukin-8
• Lactones
• NF-kappa B
• Sesquiterpenes
• Vascular Endothelial Growth Factor A
• parthenolide

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Immunohistochemistry
• Interleukin-8 (analysis)
• Lactones (pharmacology)
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Phosphorylation
• Sesquiterpenes (pharmacology)
• Time Factors
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor A (analysis)
• Xenograft Model Antitumor Assays