Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB.
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.
Oka
Daizo
D
Department of Urology, Osaka University, Graduate School of Medicine, Suita-city, Osaka, Japan.
Nishimura
Kazuo
K
Shiba
Masahiro
M
Nakai
Yasutomo
Y
Arai
Yasuyuki
Y
Nakayama
Masashi
M
Takayama
Hitoshi
H
Inoue
Hitoshi
H
Okuyama
Akihiko
A
Nonomura
Norio
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000032:analysis; D007783:Lactones / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012717:Sesquiterpenes / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D016209:Interleukin-8; D007783:Lactones; D016328:NF-kappa B; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C002669:parthenolide