Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures.
The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10(-7) M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10(-5) M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10(-5) M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.
Zwergel
T
T
Clinic and Department of Urology and Pediatric Urology, University of the Saarland, Germany. thomas.zwergel@uniklinik-saarland.de
Tahmatzopoulos
A
A
Wullich
B
B
Zwergel
U
U
Stöckle
M
M
Unteregger
G
G
D000230:Adenocarcinoma / Q000473:pathology*; D000726:Androgen Antagonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009842:Oligopeptides; D011480:Protease Inhibitors; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C014290:hydroxyflutamide; D005485:Flutamide