title: Inhibition of aromatase activity and growth suppression by 4-methoxy-4-androstene-3,17-dione in an androgen sensitive human prostatic carcinoma cell line.
abstract: Aromatization of testosterone to estradiol was investigated in a human prostatic carcinoma cell line, LNCaP. A saturable, dose and time-dependent aromatization of testosterone was observed. Kinetic parameters, Km (201 nM) and V(max) (0.76 pmol/h) per mg) and also the inhibition constants (Ki) for various aromatase inhibitors were calculated from standard Lineweaver-Burke plots. The steroidal aromatase inhibitor 4-hydroxy-4-androstene-3,17-dione (4-OHA) and its derivative, 4-methoxy-4-androstene-3,17-dione (4-OMA), inhibited aromatization of testosterone in a competitive pattern of inhibition. The derivative 4-OMA is the stronger inhibitor of the two, with an apparent Ki of 1.12 microM, whereas the apparent Ki of 4-OHA is 3.28 microM. Long term incubation with 4-OMA suppressed proliferative activity of LNCaP cells in the presence of physiological levels of testosterone (10(-10) M to 10(-7) M). In contrast, 4-OHA was a growth promoter. These results suggest a potential role for aromatase in hormone responsive prostate cancer.
authors.affiliation: Department of Urology, University of Miami School of Medicine, FL 33101, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Block
authors.forename: N L
authors.initials: NL
authors.lastname: Block
authors.forename: B L
authors.initials: BL
authors.lastname: Lokeshwar
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D002455:Cell Division / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D013739:Testosterone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D016895:Culture Media, Serum-Free; D013739:Testosterone; D000735:Androstenedione; D001141:Aromatase; C014594:formestane