| Chemopreventive actions by enterolactone and 13 VIOXX-related lactone derivatives in H295R human adrenocortical carcinoma cells. | |
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MedLine Citation:
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PMID: 19913079 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cytochrome P450c17 (CYP17) has been linked to various hormone-related diseases, including breast cancer, thus being a potential target for cancer chemoprevention. We studied the naturally occurring phytochemical enterolactone (ENL) and 13 VIOXX-related lactone derivatives (CRI-1 to CRI-13) for their effects on CYP17 activity and expression and on cell cycle status in the human H295R adrenocorticocarcinoma cell line. Of the tested compounds, only CRI-3, -7, -10 and -12 showed to be inhibitors of CYP17 activity in H295R cells. This inhibition was not due to decreased mRNA expression, but was apparently caused by post-translational modification of the CYP17 enzyme. The MAPK kinase (MEK) inhibitor PD98059 induced CYP17 activity by 24%, while co-incubation of the CRI-s with PD98059, reduced CYP17 activity even further than the reduction caused by the CRI-s alone. In addition, CRI-3, -7, -10 and -12 arrested the cell cycle in the G(2)/M phase. The structure-activity similarities of the CRI-s with known micro-tubule binding agents strongly suggest that cell cycle arrest is a result of interaction with tubulin. We conclude that the proposed cancer chemopreventive actions of ENL are not mediated through interaction with CYP17 or cell cycle status. Of the VIOXX-related lactone derivatives, CRI-7 could prove useful in the prevention of hormone-dependent cancers, such as breast cancer, since in vitro it shows low cytotoxicity, it is a potent inhibitor of CYP17 activity and strong inducer of cell cycle arrest. |
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Authors:
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Majorie B M van Duursen; Sandra M Nijmeijer; Somsak Ruchirawat; Martin van den Berg |
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Publication Detail:
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Type: Journal Article Date: 2009-11-11 |
Journal Detail:
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Title: Toxicology letters Volume: 192 ISSN: 1879-3169 ISO Abbreviation: Toxicol. Lett. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-02-15 Completed Date: 2010-03-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7709027 Medline TA: Toxicol Lett Country: Netherlands |
Other Details:
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Languages: eng Pagination: 271-7 Citation Subset: IM |
Copyright Information:
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Copyright 2009 Elsevier Ireland Ltd. All rights reserved. |
Affiliation:
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Endocrine Toxicology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands. m.vanduursen@uu.nl |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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4-Butyrolactone
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analogs & derivatives*,
pharmacology Adrenal Cortex Neoplasms / enzymology*, physiopathology Adrenocortical Carcinoma / enzymology*, physiopathology Cell Cycle / drug effects Cell Line, Tumor Enzyme Induction / drug effects Flavonoids / pharmacology Gene Expression / drug effects Humans Lactones / pharmacology* Lignans / pharmacology* Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors Neoplasms, Hormone-Dependent / prevention & control Phytoestrogens / pharmacology* Protein Processing, Post-Translational / drug effects Steroid 17-alpha-Hydroxylase / antagonists & inhibitors, biosynthesis, drug effects* Structure-Activity Relationship Sulfones / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Flavonoids; 0/Lactones; 0/Lignans; 0/PD 98059; 0/Phytoestrogens; 0/Sulfones; 0/rofecoxib; 76543-15-2/2,3-bis(3'-hydroxybenzyl)butyrolactone; 96-48-0/4-Butyrolactone; EC 1.14.99.9/Steroid 17-alpha-Hydroxylase; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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