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


METHODS
Ozarelix was added to cultures and toxicity, cell cycle modifications, cell viability and caspase activity were investigated.


RESULTS
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.


CONCLUSIONS
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.
Festuccia
Claudio
C
Radiobiology Laboratory, Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. claudio.festuccia@univaq.it
Dondi
Donatella
D
Piccolella
Margherita
M
Locatelli
Alessia
A
Gravina
Giovanni Luca
GL
Tombolini
Vincenzo
V
Motta
Marcella
M
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D011799:Quinazolines; D007987:Gonadotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077156:Gefitinib