Inhibition of growth and induction of apoptosis by androgens of a variant of LNCaP cell line

Here are described the effects of androgens, and other molecules known to b ind to androgen receptors (AR), on MOP cells established from the human pro state cancer cell line LNCaP. MOP cells contained AR: 100 000 binding sites /cell, K-D for 5 alpha dihydrotestosterone (DHT) 0.5 nM, size 110 kDa. The AR gene has the same repetition polymorphism in exon 1 and the T876A mutati on in exon 8 as LNCaP. The proliferation of MOP cells in culture was repres sed by the synthetic androgen 17 beta -hydroxy-17-methyl-estra-4,9,11-trien -3-one (R 1881), the antiandrogen cyproterone acetate (CYPA), estradiol (E2 ), progesterone and the synthetic progestin promegestone: 17,21 dimethyl-19 nor-4,9 pregnandiene-3,20 dione (R 5020). The number of cells recovered af ter 7 days decreased to approximate to 40% of controls. ED(70)s ranged betw een 50 pM for R 1881 to 50 nM for E2 and CYPA. Treatment with R 1881 decrea sed [H-3]thymidine incorporation into DNA and increased dramatically the do ubling time. R 1881, CYPA and E2 blocked the cell cycle between G1 and S ph ases and they induced apototosis as demonstrated by the increase of blebs o n the plasma membrane, nuclear fragmentation, TdT-mediated dUTP nick end-la beling (TUNEL)-positive cells and internucleosomal DNA breaks. In athymic n ude mice, testosterone enanthate prevented the growth of MOP tumors and, wh en tumors did develop, brought about regression. However, the tumors did no t regress completely and finally escaped treatment. In conclusion, a varian t of the LNCaP cell line has been established. With these cells it was poss ible to confirm that androgens paradoxically repress the growth of some pro state cancer cells both in culture and in vivo. In addition it is demonstra ted in culture but not in vivo, for the first time to the authors' knowledg e, that a synthetic androgen is able to induce apoptosis of cells establish ed from human prostate carcinoma. (C) 2000 Elsevier Science Ltd. All rights reserved.