6-Hydroximinoandrostenedione, a new specific inhibitor of estrogen biosynthesis and its effect on T47D human breast cancer cells.
A new male steroid hormone analogue, 6-hydroximinoandrostenedione, was obtained in 12% yield by an 8-step synthesis. The compound is cytochrome P450 aromatase-specific, inducing a Type-1 optical difference spectrum with the human placental enzyme (Ks 2.24 microM). It efficiently inhibits human cytochrome P450 aromatase (Ki 0.08 microM) in a time--and concentration--dependent manner, but no conclusive evidence was found that it also inactivates the placental enzyme. Cultured human T47D breast cancer cells have the unique capacity to convert de novo [14C]androstenedione into radioactive estrone and estradiol, as we have established by repetitive HPLC purifications of the biosynthetic products formed. A very small amount of an unidentified radioactive metabolite was also formed. We conclude that an endogenous androgen - aromatizing enzyme is present in T47D cells; a fact not previously reported for this human breast cancer cell line. Furthermore, the new aromatase inhibitor was found to cause a significant decrease in the growth of these cells. Our results indicate that: 1) growth of T47D cancer cells is estrogen-dependent, 2) substitution at the C-6 "front" face of an androst-4-ene-3-one molecule does not cause rejection of the modified C19 male steroidhormone by the aromatase enzyme, 3) the new 6-hydroximinoandrostenedione inhibitor has the potential to act as a highly specific anti-aromatase breast cancer agent.
Gervais
M
M
Department of Biochemistry, University of Sherbrooke Medical Faculty, Fleurimont, Que., Canada.
Tan
L
L
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis*; D006801:Humans; D007700:Kinetics; D013053:Spectrophotometry; D014407:Tumor Cells, Cultured / Q000187:drug effects
D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; C081771:6-hydroximino-4-androstene-3,17-dione; D000735:Androstenedione