Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo.
Inducing apoptosis via the extrinsic death receptor pathway is an attractive anti-cancer treatment strategy, however, numerous cancer cells exhibit significant resistance to death ligand stimuli. Here, we investigated the anti-neoplastic capability of proteasome inhibition, through the administration of Velcade, to synergize with a death receptor agonist in vivo. The death ligand-resistant LNCaP prostate xenograft model was utilized. Tumors were established and mice were treated with Velcade, TRAIL (TNF-Related Apoptosis Inducing Ligand) or the combined regimen. Only mice treated with a combination of Velcade and TRAIL was tumor growth inhibited with a corresponding loss of the hemorrhagic phenotype, decreased tumor cell proliferation and increased tumor cell apoptosis. Next, to determine if the extrinsic pathway is critical for mediating the anti-tumor efficacy that can be achieved in some cell types with Velcade treatment alone, the death receptor sensitive PC-3 xenograft model was used. PC-3 tumors exhibited a 54% decrease in tumor volume in response to Velcade, while c-FLIP overexpressing PC-3 xenografts were resistant to the treatment. These findings suggest that the extrinsic apoptotic pathway can mediate the anti-tumor effects of Velcade and support the therapeutic use of proteasome inhibition in combination with a death receptor stimulus in the treatment of prostate cancer.
Christian
Perry A
PA
Markey Cancer Center and the Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, 40514, USA.
Thorpe
Jeffery A
JA
Schwarze
Steven R
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib