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Epidithiodiketopiperazines block the interaction between hypoxia-inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2009 Sep 25; Vol. 284 (39), pp. 26831-8. Date of Electronic Publication: 2009 Jul 09. - Publication Year :
- 2009
-
Abstract
- The hypoxic response in humans is regulated by the hypoxia-inducible transcription factor system; inhibition of hypoxia-inducible factor (HIF) activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-alpha and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1alpha and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn(2+) through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300, causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated a decrease in vascular endothelial growth factor and antiproliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion-binding protein targets involved in gene expression.
- Subjects :
- Binding Sites
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Disulfides chemistry
Dose-Response Relationship, Drug
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit chemistry
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Indole Alkaloids chemistry
Models, Chemical
Models, Molecular
Molecular Sequence Data
Molecular Structure
Protein Binding drug effects
Protein Structure, Tertiary
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Vascular Endothelial Growth Factor A metabolism
Zinc chemistry
p300-CBP Transcription Factors chemistry
p300-CBP Transcription Factors genetics
Disulfides pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Indole Alkaloids pharmacology
Zinc pharmacology
p300-CBP Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 284
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19589782
- Full Text :
- https://doi.org/10.1074/jbc.M109.009498