Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells.
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Hui AM, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA
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.
- PubMed ID
- 15604281 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Custirsen Investigational ACAP2 23527 upregulated CC-8490 results in increased expression of ACAP2 mRNA 3q29 Custirsen Investigational ACTR1B 10120 downregulated CC-8490 results in decreased expression of ACTR1B mRNA 2q11.2 Custirsen Investigational ATF3 467 upregulated CC-8490 results in increased expression of ATF3 mRNA 1q32.3 Custirsen Investigational BCL6 604 upregulated CC-8490 results in increased expression of BCL6 mRNA 3q27.3 Custirsen Investigational CDK1 983 downregulated CC-8490 results in decreased expression of CDK1 mRNA 10q21.2 Custirsen Investigational CEBPB 1051 upregulated CC-8490 results in increased expression of CEBPB mRNA 20q13.13 Custirsen Investigational CTBS 1486 upregulated CC-8490 results in increased expression of CTBS mRNA 1p22.3 Custirsen Investigational CXCL8 3576 upregulated CC-8490 results in increased expression of CXCL8 mRNA 4q13.3 Custirsen Investigational DAG1 1605 upregulated CC-8490 results in increased expression of DAG1 mRNA 3p21.31 Custirsen Investigational DDIT3 1649 upregulated CC-8490 results in increased expression of DDIT3 mRNA 12q13.3 Custirsen Investigational DDX42 11325 upregulated CC-8490 results in increased expression of DDX42 mRNA 17q23.3 Custirsen Investigational DUSP5 1847 upregulated CC-8490 results in increased expression of DUSP5 mRNA 10q25.2 Custirsen Investigational EIF5 1983 upregulated CC-8490 results in increased expression of EIF5 mRNA 14q32.32 Custirsen Investigational GADD45A 1647 upregulated CC-8490 results in increased expression of GADD45A mRNA 1p31.3 Custirsen Investigational GFPT1 2673 upregulated CC-8490 results in increased expression of GFPT1 mRNA 2p13.3 Custirsen Investigational IER3 8870 upregulated CC-8490 results in increased expression of IER3 mRNA 6p21.33 Custirsen Investigational IL6 3569 upregulated CC-8490 results in increased expression of IL6 mRNA 7p15.3 Custirsen Investigational KYNU 8942 upregulated CC-8490 results in increased expression of KYNU mRNA 2q22.2 Custirsen Investigational LARP6 55323 upregulated CC-8490 results in increased expression of LARP6 mRNA 15q23 Custirsen Investigational MCM7 4176 downregulated CC-8490 results in decreased expression of MCM7 mRNA 7q22.1 Custirsen Investigational NFKB1 4790 upregulated CC-8490 results in increased expression of NFKB1 mRNA 4q24 Custirsen Investigational PCLAF 9768 downregulated CC-8490 results in decreased expression of PCLAF mRNA 15q22.31 Custirsen Investigational PGGT1B 5229 upregulated CC-8490 results in increased expression of PGGT1B mRNA 5q22.3 Custirsen Investigational PLEKHM2 23207 upregulated CC-8490 results in increased expression of PLEKHM2 mRNA 1p36.21 Custirsen Investigational RND3 390 upregulated CC-8490 results in increased expression of RND3 mRNA 2q23.3 Custirsen Investigational SLC3A2 6520 upregulated CC-8490 results in increased expression of SLC3A2 mRNA 11q12.3 Custirsen Investigational SOD2 6648 upregulated CC-8490 results in increased expression of SOD2 mRNA 6q25.3 Custirsen Investigational SPHK1 8877 upregulated CC-8490 results in increased expression of SPHK1 mRNA 17q25.2 Custirsen Investigational STC2 8614 downregulated CC-8490 results in decreased expression of STC2 mRNA 5q35.2 Custirsen Investigational TOP1 7150 upregulated CC-8490 results in increased expression of TOP1 mRNA 20q12 Custirsen Investigational WTAP 9589 upregulated CC-8490 results in increased expression of WTAP mRNA 6q25.3 Tamoxifen Approved ACAP2 23527 upregulated Tamoxifen results in increased expression of ACAP2 mRNA 3q29 Tamoxifen Approved ACTR1B 10120 downregulated Tamoxifen results in decreased expression of ACTR1B mRNA 2q11.2 Tamoxifen Approved ATF3 467 upregulated Tamoxifen results in increased expression of ATF3 mRNA 1q32.3 Tamoxifen Approved BCL6 604 upregulated Tamoxifen results in increased expression of BCL6 mRNA 3q27.3 Tamoxifen Approved CDK1 983 downregulated Tamoxifen results in decreased expression of CDK1 mRNA 10q21.2 Tamoxifen Approved CEBPB 1051 upregulated Tamoxifen results in increased expression of CEBPB mRNA 20q13.13 Tamoxifen Approved CTBS 1486 upregulated Tamoxifen results in increased expression of CTBS mRNA 1p22.3 Tamoxifen Approved CXCL8 3576 upregulated Tamoxifen results in increased expression of CXCL8 mRNA 4q13.3 Tamoxifen Approved DAG1 1605 upregulated Tamoxifen results in increased expression of DAG1 mRNA 3p21.31 Tamoxifen Approved DDIT3 1649 upregulated Tamoxifen results in increased expression of DDIT3 mRNA 12q13.3 Tamoxifen Approved DDX42 11325 upregulated Tamoxifen results in increased expression of DDX42 mRNA 17q23.3 Tamoxifen Approved DUSP5 1847 upregulated Tamoxifen results in increased expression of DUSP5 mRNA 10q25.2 Tamoxifen Approved EIF5 1983 upregulated Tamoxifen results in increased expression of EIF5 mRNA 14q32.32 Tamoxifen Approved GADD45A 1647 upregulated Tamoxifen results in increased expression of GADD45A mRNA 1p31.3 Tamoxifen Approved GFPT1 2673 upregulated Tamoxifen results in increased expression of GFPT1 mRNA 2p13.3 Tamoxifen Approved IER3 8870 upregulated Tamoxifen results in increased expression of IER3 mRNA 6p21.33 Tamoxifen Approved IL6 3569 upregulated Tamoxifen results in increased expression of IL6 mRNA 7p15.3 Tamoxifen Approved KYNU 8942 upregulated Tamoxifen results in increased expression of KYNU mRNA 2q22.2 Tamoxifen Approved LARP6 55323 upregulated Tamoxifen results in increased expression of LARP6 mRNA 15q23 Tamoxifen Approved MCM7 4176 downregulated Tamoxifen results in decreased expression of MCM7 mRNA 7q22.1 Tamoxifen Approved NFKB1 4790 upregulated Tamoxifen results in increased expression of NFKB1 mRNA 4q24 Tamoxifen Approved PCLAF 9768 downregulated Tamoxifen results in decreased expression of PCLAF mRNA 15q22.31 Tamoxifen Approved PGGT1B 5229 upregulated Tamoxifen results in increased expression of PGGT1B mRNA 5q22.3 Tamoxifen Approved PLEKHM2 23207 upregulated Tamoxifen results in increased expression of PLEKHM2 mRNA 1p36.21 Tamoxifen Approved RCAN1 1827 upregulated Tamoxifen results in increased expression of RCAN1 mRNA 21q22.12 Tamoxifen Approved RND3 390 upregulated Tamoxifen results in increased expression of RND3 mRNA 2q23.3 Tamoxifen Approved SLC3A2 6520 upregulated Tamoxifen results in increased expression of SLC3A2 mRNA 11q12.3 Tamoxifen Approved SOD2 6648 upregulated Tamoxifen results in increased expression of SOD2 mRNA 6q25.3 Tamoxifen Approved SPHK1 8877 upregulated Tamoxifen results in increased expression of SPHK1 mRNA 17q25.2 Tamoxifen Approved STC2 8614 downregulated Tamoxifen results in decreased expression of STC2 mRNA 5q35.2 Tamoxifen Approved TOP1 7150 upregulated Tamoxifen results in increased expression of TOP1 mRNA 20q12 Tamoxifen Approved WTAP 9589 upregulated Tamoxifen results in increased expression of WTAP mRNA 6q25.3