Suppressive effects of dehydroepiandrosterone and the nuclear factor-κB inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo

Abstract

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-B (NF-B) 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-B-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-B-mediated gene transcription.

Myeloperoxidase Expression as a Potential Determinant of Parthenolide-Induced Apoptosis in Leukemia Bulk and Leukemia Stem Cells

“…‫,ء‬ P Ͻ 0.05; ‫,ءء‬ P Ͻ 0.01. (Khoshnan et al, 2000;Taguchi et al, 2006), were documented only in the MPO-high leukemia cells. PTL-induced truncation of the BH3-only protein Bid (tBID) and induction of the proapoptotic targets PUMA and Bak as well as phosphorylation of p-JNK were also observed selectively in the MPO-high leukemia cells.…”

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

“…S4, see section on supplementary data given at the end of this article). Therefore, to be able to further functionally characterize the pituitary tumor SP and to explore its TSC-associated phenotype, we turned to a well-established pituitary tumor cell line, the mouse corticotrope AtT20, which has previously been shown to grow tumors after s.c. implantation in immunodeficient mice (Taguchi et al 2006).…”

“…The s.c. injection of 5!10 5 cells resulted in a gradually developing tumor ( Supplementary Fig. S5A, see section on supplementary data given at the end of this article), which was palpable after 15-20 days and further expanded in volume until the mouse became moribund, most probably as a result of corticoid overproduction because of increased adrenal stimulation by the AtT20-produced ACTH (Taguchi et al 2006). A SP remained present in the AtT20-derived xenograft tumors (as analyzed after 50-55 days), although the proportion was lower than that in the cell line in culture (0.5% versus 1%; nZ3).…”

Inhibition of heat shock protein 90 decreases ACTH production and cell proliferation in AtT-20 cells

“…AtT-20-xenografted mice produce high levels of plasma corticosterone levels and have been used as an animal model of ACTH-dependent Cushing's disease (Taguchi et al [36], Fukuoka et al [37]). AtT-20-xenografted mice were treated with CCT018159 to determine its effects on corticotroph tumor growth and function in vivo.…”