The effects of the selective estrogen receptor modulators, methyl‐piperidino‐pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus

Abstract

Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P <or= 0.0001-0.001). To determine the in vivo uterine effects of these compounds, ovariectomized wild-type (WT) and estrogen receptor-beta knockout (ERbetaKO) mice were treated with 25, 50, 100, or 150 microg of each compound. Although raloxifene caused no significant increase in uterine weight, the presumptive ERalpha antagonist, MPP (25-150 microg) increased uterine weight, and cell proliferation significantly relative to vehicle control in WT and ERbetaKO mice (P <or= 0.001). However, MPP did not increase uterine wet weight as effectively as beta-estradiol (P <or= 0.0001), and administration of either 50 microg of MPP or raloxifene effectively reversed the positive effects of 50 and 100 microg beta-estradiol. Unexpectedly, in view of the in vitro studies, MPP and raloxifene treatment of ovariectomized mice did not induce apoptosis of the luminal epithelial cells but rather these compounds induced apoptosis of the underlying uterine stromal cells. These results demonstrate that MPP and raloxifene can exert apparently contrasting in vitro versus in vivo effects, and that they have mixed agonist/antagonist action on murine uterine ERalpha in vivo.

Selective estrogen receptor α activation disrupts sex organ differentiation and induces expression of vitellogenin II and very low-density apolipoprotein II in Japanese quail embryos

“…However, treatment with MPP alone slightly induced the expression of apoVLDL II mRNA, indicating that MPP also has some agonistic action on ERa in the Japanese quail. In accordance with this, recent results suggest that MPP acts as a mixed agonist/antagonist on ERa in the mouse uterus (Davis et al 2006). In our study, we did not detect any other agonistic effects by MPP than the effect on apoVLDL II expression.…”

Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in Mozambique tilapia

“…The studies described here are confined to the adult tilapia liver; E 2 and its receptors also have well-defined roles in sex differentiation and ontogeny of fishes, as well as in other tissues such as brain and gonads [36][37][38]. In mammals, the actions of PPT, DPN, and MPP vary, depending on the species, physiological conditions, dosing method, and tissue [39][40][41][42]. Our studies have shown that, in particular, the mammalian ER␤ agonist DPN has the ability to act as a selective ER agonist, likely for ER␣, in tilapia.…”

The combination of raloxifene and epigallocatechin gallate suppresses growth and induces apoptosis in MDA-MB-231 cells

“…It has been demonstrated that raloxifene induces apoptosis in a variety of cancer cells including prostate (Kim et al, 2002a,b;Shazer et al, 2006), uterine leiomyoma (Liu et al, 2007;Palomba et al, 2005), endometrial (Davis et al, 2006), myeloma (Olivier et al, 2006), bladder (Kim et al, 2002c), as well as ERα+ and ERα− breast cancer cells (Werner et al, 2005). Additionally, other groups have shown that the efficacy of raloxifene is increased upon co-administration of 13-cis retinoic acid (Anzano et al, 1996).…”