Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.
Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.
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卡非佐米和伏立诺他在 T 细胞白血病/淋巴瘤中的治疗潜力和功能相互作用。
DOI：
10.18632/oncotarget.8667
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发表时间：
2016-05-17
期刊：
影响因子：
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通讯作者：
Shi J
中科院分区：
文献类型：
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作者：
Gao M;Chen G;Wang H;Xie B;Hu L;Kong Y;Yang G;Tao Y;Han Y;Wu X;Zhang Y;Dai B;Shi J
我们先前表明，蛋白酶体抑制剂卡非佐米和组蛋白脱乙酰酶抑制剂（HDACI）伏立诺他在体外协同诱导一种T细胞白血病细胞系的细胞凋亡，这意味着卡非佐米和伏立诺他联合治疗作为人类T细胞白血病/淋巴瘤潜在治疗策略的可能性。在这里，我们报告了卡非佐米和伏立诺他的联合治疗增强了细胞凋亡，诱导了G2-M期阻滞、活性氧（ROS）产生的显著增加，并激活了丝裂原活化蛋白激酶（MAPK）家族的成员，包括应激活化激酶JNK、p38 MAPK和ERK 1/2。ROS清除剂N-乙酰半胱氨酸（NAC）可阻断卡非佐米/伏立诺他介导的细胞凋亡。JNK抑制剂SP 600125和p38 MAPK抑制剂SB 203580而不是MEK 1/2抑制剂U 0126显著减弱了卡非佐米/伏立诺他诱导的细胞凋亡，表明p38 MAPK和JNK激活有助于卡非佐米和伏立诺他诱导的细胞凋亡。这通过短发夹（shRNA）RNA敲低p38 MAPK和JNK进一步证实。有趣的是，ROS清除剂NAC减弱了卡非佐米/伏立诺他介导的p38 MAPK和JNK活化。然而，p38 MAPK shRNA而不是JNK shRNA减少了卡非佐米/伏立诺他介导的ROS产生。相比之下，p38 MAPK的过表达显着增加了卡非佐米/伏立诺他介导的活性氧的产生，表明活性氧和p38 MAPK途径之间存在放大环。卡非佐米和伏立诺他的联合治疗增强了其在人异种移植模型以及人原代T细胞白血病/淋巴瘤细胞中的个体抗肿瘤活性。这些数据表明了卡非佐米与伏立诺他联合治疗人T细胞白血病/淋巴瘤的潜在临床获益和潜在分子机制。
We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro, implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G2-M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma.
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11.4
作者：
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通讯作者：
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