Chemopreventive actions by enterolactone and 13 VIOXX-related lactone derivatives in H295R human adrenocortical carcinoma cells.
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.
van Duursen
Majorie B M
MB
Endocrine Toxicology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands. m.vanduursen@uu.nl
Nijmeijer
Sandra M
SM
Ruchirawat
Somsak
S
van den Berg
Martin
M
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000306:Adrenal Cortex Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D018268:Adrenocortical Carcinoma / Q000201:enzymology* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D017705:Lignans / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009376:Neoplasms, Hormone-Dependent / Q000517:prevention & control; D048789:Phytoestrogens / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*
D005419:Flavonoids; D007783:Lactones; D017705:Lignans; D048789:Phytoestrogens; D013450:Sulfones; C116926:rofecoxib; D013254:Steroid 17-alpha-Hydroxylase; D020929:Mitogen-Activated Protein Kinase Kinases; D015107:4-Butyrolactone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone