Targeting estrogen receptor subtypes (ERα and ERß) with selective ER modulators in ovarian cancer.

Ovarian cancer cells express both estrogen receptor α (ERα) and ERß, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERα compared with ERß, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. Sodium 3'-(1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) assay revealed that treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) (ERα antagonist) or 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) (ERß agonist) significantly suppressed cell growth in both cell lines. In contrast, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) (ERα agonist) or 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-3-yl]phenol (PHTPP) (ERß antagonist) significantly enhanced cell growth. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

Butein downregulates phorbol 12-myristate 13-acetate-induced COX-2 transcriptional activity in cancerous and non-cancerous breast cells.

Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Cyclooxygenase (COX) converts arachidonic acid to prostanoids, and increased expression of its isoform COX-2 has been observed in breast cancer tissues. It has been suggested that COX inhibitors can be used as chemopreventive agents against breast carcinogenesis. This study examined the potential suppressive effect of the flavonoid on phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in the non-tumorigenic MCF-10A and cancerous MCF-7 breast cells. Immunoblot and mRNA analyses revealed that butein at or below 10 µM significantly inhibited PMA-induced COX-2 expression in these breast cells. The blocking of the PKC signaling pathway appeared to be the underlying mechanism. Butein treatment reduced the amount of phospho-mitogen activated protein kinase (MAPK) ERK-1/2, and the total activity of PKC. Activated ERKs might trigger the transcriptional activation of COX-2. Reporter gene assays as well as electrophoretic mobility shift assays (EMSA) illustrated that butein inhibited transcription of this gene. This study showed that butein down-regulated PMA-induced COX-2 expression in both cancerous and non-cancerous breast cells, and such findings could provide the basis for pharmaceutical development of butein.