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Chemopreventive actions by enterolactone and 13 VIOXX-related lactone derivatives in H295R human adrenocortical carcinoma cells
- Source :
- Toxicology Letters, 192(3), 271. Elsevier Ireland Ltd.
- Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
endocrine system
Cell cycle checkpoint
Neoplasms, Hormone-Dependent
Gene Expression
Phytoestrogens
Biology
Toxicology
Lignans
chemistry.chemical_compound
Lactones
Structure-Activity Relationship
Enterolactone
4-Butyrolactone
Internal medicine
Cell Line, Tumor
medicine
Adrenocortical Carcinoma
Humans
Sulfones
Cytotoxicity
chemistry.chemical_classification
Flavonoids
Mitogen-Activated Protein Kinase Kinases
Cell Cycle
Cancer
Steroid 17-alpha-Hydroxylase
General Medicine
Cell cycle
medicine.disease
In vitro
Adrenal Cortex Neoplasms
Endocrinology
Enzyme
chemistry
Cell culture
Enzyme Induction
Cancer research
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 03784274
- Database :
- OpenAIRE
- Journal :
- Toxicology Letters, 192(3), 271. Elsevier Ireland Ltd.
- Accession number :
- edsair.doi.dedup.....12e5922bf18eeca87d8cb4151ed81493