The Proliferative Effect of “Anti-Androgens” on the Androgen-Sensitive Human Prostate Tumor Cell Line LNCaP

Abstract

The effect of steroidal and nonsteroidal "anti-androgens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 X 10(-9) M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 X 10(-8) M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17 beta (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 X 10(-10) M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 X 10(-10) M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…These cells may respond to androgen/AR signals differentially depending on different environments (Olea et al, 1990) and exhibited variants. For example, the ARexpressing LNCaP-FGC and LNCaP-LNO cell lines isolated from the same lymph node metastatic tumor (Horoszewicz et al, 1983) exhibited different and opposite proliferation responses toward androgen (Olea et al, 1990, Soto et al, 1995. Proliferation of LNCaP-FGC cells was stimulated by a low concentration and suppressed by a high concentration of androgen, whereas proliferation of LNCaP-LNO cells was suppressed by physiological concentrations of androgen.…”

Ca2+ Pools and Cell Growth

“…Androgens are considered to play a crucial role in the development and progression of prostate cancer, since men castrated before puberty do not develop this disease (11). Moreover, antiandrogens inhibit prostate growth in vitro (12) and in vivo (13). It is also known that, testosterone is irreversibly converted to dihydrotestosterone (DHT) within the prostate gland by the 5-␣a-reductase enzyme, and that DHT is the active androgen in the prostate (14).…”

Androgen receptor coregulators NOCR1, TIF2, and ARA70 may account for the hydroxyflutamide insensitivity of prostate cancer cells

“…It is believed that LNCaP cells gain flutamide resistance by AR mutation (T877A). In 1990, Olea et al [13] reported that flutamide at concentrations of 3 9 10 -8 M or higher was effective in inducing proliferation of LNCaP-FGC cells. However, they did not mention the time of hydroxyflutamide treatment.…”

“…The second is flutamide's shutoff effect. Olea et al [13] reported that anti-androgens did not trigger a proliferative shutoff response, whereas androgens do. Furthermore, dihydrotestosterone may act on the LNCaP cells synergistically with hydroxyflutamide in stimulating cell proliferation.…”