Finasteride inhibits DHT binding to AR and AR activity in LNCaP and C4-2 cells, but not in VCaP cells. The difference in the AR activity response is not due to sensitivity of the cells to finasteride in blocking the conversion of testosterone to DHT, since all cell cultures were treated with the same level of exogenous DHT. LNCaP and C4-2 cells express the T877A mutant AR, while VCaP cells express the wild-type AR. Our data therefore suggest that the AR antagonistic effect of finasteride may be specific to the mutant AR. The conclusion is supported by the PC-3 experiment. PC-3 cells are naturally AR-null. When PC-3 cells were transfected with either the mutant or wild-type AR, only the mutant AR-expressing cells were sensitive to finasteride inhibition of DHT binding. The observation is consistent with the interpretation that finasteride interferes directly with the binding of DHT to the mutant AR, and that co-regulators of AR-DHT binding are unlikely to play a major role in this process. The biological significance of the antiandrogenic effect of finasteride is reflected by growth inhibition of LNCaP cells. In contrast, VCaP cells are not responsive to finasteride in this regard. Whether finasteride is able to antagonize other AR ligand binding domain mutants, in addition to the T877A mutant, is currently under investigation. Although the prevalence of AR mutants is low in early stage prostate cancer, it escalates to the range of 20–40% in hormone-refractory or castration-resistant prostate cancer.
In some cases, sufficient quantities of DHT may be produced to maintain AR function. If so, does it matter then whether AR mutants use either non-androgen steroids or DHT as a ligand? This question remains to be settled. Regardless, it would be informative to find out whether finasteride could interfere with the binding of AR mutants to nonandrogen steroid, e.g., dehydroepiandrosterone
