Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.
BACKGROUND
Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line.


METHODS
LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined.


RESULTS
Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride.


CONCLUSIONS
Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens.
Lazier
C B
CB
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada. cblazier@dal.ca
Thomas
L N
LN
Douglas
R C
RC
Vessey
J P
JP
Rittmaster
R S
RS
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000494:pharmacology; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001378:Azasteroids / Q000494:pharmacology*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D018120:Finasteride / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001378:Azasteroids; D004791:Enzyme Inhibitors; D008024:Ligands; D011944:Receptors, Androgen; D013739:Testosterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D017430:Prostate-Specific Antigen; D000068538:Dutasteride