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Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells.


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Website: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15604281&dopt=Abstract

Posted on: 12/28/2004

Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells.

Cancer Res. 2004 Dec 15;64(24):9115-23.

Hui AM, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA.

Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, and Celgene, San Diego, California, USA.

Tamoxifen, a member of the selective estrogen receptor modulator (SERM) family, is widely used in the treatment of estrogen receptor (ER)-expressing breast cancer. It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells, but whether this effect is drug specific or represents a general property of SERMs is unknown. In this study, we demonstrate that tamoxifen and CC-8490, a novel benzopyranone with SERM activity, induce glioma cell apoptosis in a dose- and time-dependent manner. Moreover, administration of tamoxifen and CC-8490 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models. None of the eight glioma cell lines examined express either ER-alpha or -beta, suggesting the mechanism for tamoxifen- and CC-8490-induced glioma cell apoptosis is independent of the ER signaling pathway. Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and CC-8490, and not by other apoptotic stimuli, including nuclear factor (NF)-kappaB with its target genes IEX-3, SOD2, IL6, and IL8. We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis, suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity. These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway. PMID: 15604281 [PubMed - in process]



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