Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors

Abstract

Antagonistic or agonistic analogues of gonadotropin-releasing hormone are extensively used for the treatment of advanced hormone-dependent prostate cancer. However, the majority of recurrent prostate tumors is androgen independent. This study explored the in vitro effects on DU145 and PC3 cell lines, two models of androgen-independent prostate cancer, of a fourth generation GnRH antagonist (Ozarelix). Ozarelix was added to cultures and toxicity, cell cycle modifications, cell viability and caspase activity were investigated. Ozarelix showed antiproliferative effects and produced an accumulation of cells in G2/M cell cycle phase. Apoptosis was related with caspase-8-dependent caspase 3 activation with down-regulation of c-FLIP (L) and a sensitization to TRAIL-induced apoptosis linked also to increased expression and activity of death receptors DR4/5 and Fas. TRAIL-resistant cancer cells can be sensitized to TRAIL by Ozarelix. This effect may be achieved by the activation of apoptotic pathway improving the therapeutic effects in androgen independent tumor cell lines. However, a better understanding of molecular mechanisms by which GnRH antagonists may act in androgen independent models is necessary.