Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation
Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation
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DOI：
10.1007/s00262-008-0512-7
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发表时间：
2008-12-01
影响因子：
5.8
通讯作者：
Stein, Bernd
中科院分区：
文献类型：
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作者：
Zhu, Dan;Corral, Laura G.;Stein, Bernd
Revlimid（R）（来那度胺，CC-5013）和CC-4047是IMiDs（R）免疫调节药物，已被描述为具有免疫调节特性和抗肿瘤活性。在这里，我们报告了CC-5013和CC-4047在PBMC和肿瘤细胞的共培养模型中对肿瘤细胞的促凋亡作用。CC-5013和CC-4047在K562/PBMC共培养模型中增强PBMC活性，导致肿瘤细胞凋亡。我们还证明了PBMC中的自然杀伤（NK）细胞群在诱导K562细胞凋亡中是必不可少的。观察到CC-5013和CC-4047增加NK和自然杀伤T（NKT）细胞群，同时沿着NK细胞CD 56粘附标志物的调节。此外，我们的数据表明，CC-4047的NK激活依赖于PBMC的其他细胞类型。我们将K562/PBMC共培养模型的应用扩展到其他血液系统肿瘤和实体瘤。在Raji/PBMC共培养模型中，CC-5013和CC-4047剂量依赖性地增加肿瘤细胞凋亡。用利妥昔单抗预处理Raji细胞进一步增强CC-5013或CC-4047处理的PBMC诱导的凋亡。此外，CC-5013和CC-4047在PC-3/PBMC共培养物中显著增加PC-3前列腺癌细胞凋亡，无论是作为单一药剂还是与多西他赛组合。总之，结果表明，共培养模型是评估这些化合物的抗肿瘤活性的合适的细胞系统。我们的研究结果支持CC-5013和CC-4047在复发性NHL中与利妥昔单抗和前列腺癌中与多西他赛的临床评价。
Revlimid (R) (Lenalidomide, CC-5013) and CC-4047 are IMiDs (R) immunomodulatory drugs that have been described as having immunomodulatory properties and anti-tumor activity. Here we report proapoptotic effects of CC-5013 and CC-4047 on tumor cells in a co-culture model of PBMC and tumor cells. CC-5013 and CC-4047 enhanced PBMC activity leading to tumor cell apoptosis in K562/PBMC co-culture model. We also demonstrate that the natural killer (NK) cell population of PBMC was essential in inducing K562 apoptosis. Increases of NK and natural killer T (NKT) cell populations by CC-5013 and CC-4047 was observed along with modulation of NK cell CD56 adhesion marker. In addition, our data indicate that NK activation by CC-4047 was dependent on other cell types of PBMC. We expanded the application of K562/PBMC co-culture model to other hematological and solid tumors. In Raji/PBMC co-culture model, CC-5013 and CC-4047 dose-dependently augmented tumor cell apoptosis. Pre-treatment of Raji cells with Rituximab further enhanced apoptosis induced by CC-5013 or CC-4047-treated PBMC. Moreover, CC-5013 and CC-4047 significantly increased PC-3 prostate cancer cell apoptosis in PC-3/PBMC co-culture, either as single agent or in combination with Docetaxel. Together, the results reveal that co-culture models are suitable cellular systems to assess anti-tumor activities of these compounds. Our findings support clinical evaluation of CC-5013 and CC-4047 in relapsed NHL with Rituximab and in prostate cancer with Docetaxel.