Di-(2-ethylhexyl) phthalate suppresses tamoxifen-induced apoptosis in GH3 pituitary cells

Abstract

Tamoxifen, an estrogen receptor antagonist, has been clinically used as an antitumor drug and induces apoptosis in GH3 pituitary cells. Although di-(2-ethylhexyl) phthalate (DEHP) is a well-known environmental estrogen and the exposure to this chemical is well expected, reports are limited regarding effects of DEHP on tamoxifen-induced apoptosis in pituitary cells. In the cytotoxicity assay, the reduced cell viability in tamoxifen-treated GH3 cells was reversed by DEHP (250 microM) treatment for 4 days. To characterize cell death, cells were stained using Hoechst 33258. Apoptotic morphological change such as chromatin condensation induced by tamoxifen was suppressed by treatment with DEHP. Flow cytometric analysis revealed that the number of apoptotic cells induced by tamoxifen was significantly decreased by DEHP treatment. Enhanced poly (ADP-ribose) polymerase (PARP) cleavage by tamoxifen treatment was also inhibited by DEHP. These results suggest that DEHP suppresses tamoxifen-induced apoptosis in association with its estrogenic effect in GH3 cells and might counteract the therapeutic effect of tamoxifen.

The inhibition by di(2-ethylhexyl)-phthalate of erg-mediated K+ current in pituitary tumor (GH3) cells

“…Such effect is thought to be associated with its estrogenic effect, because tamoxifen, a triphenylethylene derivative, is an antagonist of estrogen receptors (Yamasaki et al 2004;Kim et al 2007;Ghisari and BonefeldJørgensen 2009). However, in our study, tamoxifen (1 lM) was not found to reverse DEHP-mediated inhibition of I K(erg) .…”

“…Previous study showed that DEHP could suppress tamoxifen-induced apoptosis in pituitary GH 3 cells (Kim et al 2007). Such effect is thought to be associated with its estrogenic effect, because tamoxifen, a triphenylethylene derivative, is an antagonist of estrogen receptors (Yamasaki et al 2004;Kim et al 2007;Ghisari and BonefeldJørgensen 2009).…”

“…DEHP was demonstrated to suppress tamoxifen-induced apoptosis possibly linked to its estrogenic effects in pituitary GH 3 cells (Yamasaki et al 2004;Kim et al 2007). This compound was noted to exert an agedependent influence on the pituitary-adrenocortical axis in vivo (Supornsilchai et al 2007).…”