Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo

被引:19
作者
Christian, Perry A.
Thorpe, Jeffery A.
Schwarze, Steven R. [1 ]
机构
[1] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40514 USA
关键词
velcade; TRAIL; apoptosis; prostate cancer; xenograft; PROTEASOME INHIBITOR BORTEZOMIB; LEUKEMIC-CELLS; SOLID TUMORS; LIGAND; DEATH; RESISTANCE; APO2L/TRAIL; MICE; DISC;
D O I
10.4161/cbt.8.1.7132
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:73 / 80
页数:8
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