Abstract：
:The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) has been implicated in the development of various human malignancies, including breast, prostate, ovary, and colon cancer. ERRalpha, bound to a co-activator protein (e.g., peroxisome proliferator receptor gamma co-activator-1alpha, PGC-1alpha), regulates cellular energy metabolism by activating transcription of genes involved in various metabolic processes, such as mitochondrial genesis, oxidative phosphorylation, and fatty acid oxidation. Accumulating evidence suggests that ERRalpha is a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor microenvironments. This report describes a novel steroidal antiestrogen (SR16388) that binds selectively to ERRalpha, but not to ERRbeta or ERRgamma, as determined using a time-resolved fluorescence resonance energy transfer assay. SR16388 potently inhibits ERRalpha's transcriptional activity in reporter gene assays, and prevents endogenous PGC-1alpha and ERRalpha from being recruited to the promoters or enhancers of target genes. Representative in vivo results show that SR16388 inhibited the growth of human prostate tumor xenografts in nude mice as a single agent at 30mg/kg given once daily and 100mg/kg given once weekly. In a combination study, SR16388 (10mg/kg, once daily) and paclitaxel (7.5mg/kg, twice weekly) inhibited the growth of prostate tumor xenografts in nude mice by 61% compared to untreated xenograft tumors. SR16388 also inhibited the proliferation of diverse human tumor cell lines after a 24-h exposure to the compound. SR16388 thus has utility both as an experimental antitumor agent and as a chemical probe of ERRalpha biology.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Duellman SJ,Calaoagan JM,Sato BG,Fine R,Klebansky B,Chao WR,Hobbs P,Collins N,Sambucetti L,Laderoute KRdoi
10.1016/j.bcp.2010.05.024subject
Has Abstractpub_date
2010-09-15 00:00:00pages
819-26issue
6eissn
0006-2952issn
1873-2968pii
S0006-2952(10)00388-6journal_volume
80pub_type
杂志文章abstract：:[Carboxyl-14C] labelled 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (I) and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (II) were synthesized and their decarboxylation was studied in mouse brain homogenate and buffer. The decarboxylation rates of (I) and (II) in the homogenate were about 6-fol...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90173-5
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
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journal_title：Biochemical pharmacology
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：1990-10-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(89)90516-9
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journal_title：Biochemical pharmacology
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pub_type： 杂志文章,评审
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journal_title：Biochemical pharmacology
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更新日期：2000-09-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
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更新日期：2010-02-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(92)90283-o
更新日期：1992-01-22 00:00:00
