Aminoglutethimide, a steroidogenesis inhibitor, abolishes hormonal induction of ornithine decarboxylase in steroidogenic tissues: evidence for its role as cAMP-dependent protein kinase inhibitor.
Aminoglutethimide (AMG), a potent inhibitor of steroidogenesis used in the treatment of breast cancer and some adrenal pathologies, abolished the induction of ornithine decarboxylase (ODC) elicited by peptide hormones and by dibutyryl-cAMP in steroidogenic tissues. This effect seems to be related to an inhibition of cAMP-dependent protein kinase (IC50 = 287 microM) rather than blockade of the steroidogenic pathway. This inhibition may explain some of the effects observed in AMG treatment which cannot be ascribed to its direct effect on the cytochrome P450scc complex or aromatase. Taking into account that ODC, the rate-limiting enzyme in polyamine synthesis, is elevated in many types of cancer and that overexpression of this enzyme is associated with cell transformation, one may speculate that the inhibitory action of AMG on protein kinase A represents a positive colateral effect of this drug in cancer therapy.
Bastida
C M
CM
Department of Biochemistry and Molecular Biology, University of Murcia, Murcia, 30100, Spain.
Tejada
F
F
Cremades
A
A
Peñafiel
R
R
D000311:Adrenal Glands / Q000187:drug effects; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006066:Gonads / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D013737:Testis / Q000378:metabolism
D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D011073:Polyamines; D000616:Aminoglutethimide; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase; D017868:Cyclic AMP-Dependent Protein Kinases; D009955:Ornithine Decarboxylase; D007654:Ketoconazole