Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo
Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo
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DOI：
10.4161/cbt.8.1.7132
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发表时间：
2009-01-01
影响因子：
3.6
通讯作者：
Schwarze, Steven R.
中科院分区：
文献类型：
--
作者：
Christian, Perry A.;Thorpe, Jeffery A.;Schwarze, Steven R.
通过外源性死亡受体途径诱导细胞凋亡是一种有吸引力的抗癌治疗策略，然而，许多癌细胞表现出对死亡配体刺激的显著抗性。在这里，我们研究了蛋白酶体抑制的抗肿瘤能力，通过万珂的管理，协同死亡受体激动剂在体内。使用死亡配体抗性LNCaP前列腺异种移植物模型。建立肿瘤，并用万珂、TRAIL（TNF相关凋亡诱导配体）或联合方案治疗小鼠。只有万珂和TRAIL联合治疗的小鼠肿瘤生长受到抑制，相应的出血表型丧失，肿瘤细胞增殖减少，肿瘤细胞凋亡增加。接下来，为了确定外源性途径是否对于介导在某些细胞类型中单独使用万珂治疗可以实现的抗肿瘤疗效至关重要，使用了死亡受体敏感性PC-3异种移植模型。PC-3肿瘤对万珂的反应是肿瘤体积减少54%，而过表达c-FLIP的PC-3异种移植物对治疗具有抗性。这些结果表明，外源性凋亡途径可介导万珂的抗肿瘤作用，并支持蛋白酶体抑制联合死亡受体刺激治疗前列腺癌。
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.