Suppressive effects of dehydroepiandrosterone and the nuclear factor-kappaB inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo.
Dehydroepiandrosterone (DHEA) is believed to have an anti-tumor effect, as well as anti-inflammatory, antioxidant, and anti-aging effects. To clarify the possible inhibitory action of DHEA on pituitary tumor cells, we tested the effects of DHEA, alone or in combination with the nuclear factor-kappaB (NF-kappaB) inhibitor parthenolide (PRT), on AtT20 corticotroph cell growth and function both in vitro and in vivo. We found that, in vitro, DHEA and PRT had potent inhibitory effects on pro-opiomelanocortin and NF-kappaB-dependent gene expression. They also suppressed the transcription activity of survivin, a representative anti-apoptotic factor, and induced apoptosis in this cell line. Furthermore, using BALB/C nude mice with xenografts of AtT20 cells in vivo, we found that the combined administration of DHEA and PRT significantly attenuated tumor growth and survivin expression. The treatment also decreased the elevated plasma corticosterone levels and ameliorated the malnutrition induced by tumor growth. Altogether, these results suggested that combined treatments of DHEA and PRT potently inhibit the growth and function of corticotroph tumor cells both in vitro and in vivo. This effect may, at least partly, be caused by the suppressive effects of these compounds, such as survivin and other inhibitor of apoptosis proteins, on NF-kappaB-mediated gene transcription.
Taguchi
T
T
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Oko-cho, Kohasu, Nankoku 783-8505, Japan. tagu@muse.ocn.ne.jp
Takao
T
T
Iwasaki
Y
Y
Nishiyama
M
M
Asaba
K
K
Hashimoto
K
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000032:analysis; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010911:Pituitary Neoplasms / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D012097:Repressor Proteins; D012717:Sesquiterpenes / Q000494:pharmacology*; D000077022:Survivin; D013739:Testosterone / Q000494:pharmacology; D014158:Transcription, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D012717:Sesquiterpenes; D000077022:Survivin; C002669:parthenolide; D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol; D011333:Pro-Opiomelanocortin; D003345:Corticosterone