Antitumor activity of cyclin‐dependent kinase inhibitor alsterpaullone in Epstein‐Barr virus‐associated lymphoproliferative disorders
Antitumor activity of cyclin‐dependent kinase inhibitor alsterpaullone in Epstein‐Barr virus‐associated lymphoproliferative disorders
复制标题
细胞周期蛋白依赖性激酶抑制剂 alsterpaulone 在 Epstein-Barr 病毒相关淋巴增殖性疾病中的抗肿瘤活性
DOI：
10.1111/cas.14241
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发表时间：
2019
期刊：
影响因子：
5.7
通讯作者：
Kimura Hiroshi
中科院分区：
文献类型：
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作者：
Watanabe Takahiro;Sato Yoshitaka;Masud H. M. Abdullah Al;Takayama Masahiro;Matsuda Hiroki;Hara Yuya;Yanagi Yusuke;Yoshida Masahiro;Goshima Fumi;Murata Takayuki;Kimura Hiroshi
eb病毒（EBV）是一种已被证实与多种免疫缺陷相关的淋巴细胞增生性疾病（lpd）有关的肿瘤病毒。尽管利妥昔单抗（一种CD20单抗）已被证明对EBV相关的lpd有效，但由于CD20−细胞的选择性扩增，长期使用该药物可能导致耐药。我们之前已经证明，细胞周期蛋白依赖性激酶（CDK）抑制剂能够特异性抑制病毒晚期基因的表达，特别是那些编码结构蛋白的基因；然而，CDK抑制剂对EBV相关lpd的治疗效果尚不清楚。在这项研究中，我们研究了CDK抑制剂是否对体内lpd具有治疗作用。在lpd小鼠模型中，用alsterpaulone（一种CDK2复合物抑制剂）治疗可提高生存期并抑制肿瘤侵袭。抑制CDK可有效诱导EBV阳性B细胞的g1细胞周期阻滞和凋亡。这些结果表明，阿斯特保龙抑制细胞周期进程，从而在体内观察到抗肿瘤作用。
Epstein‐Barr virus (EBV) is a well‐established tumor virus that has been implicated in a wide range of immunodeficiency‐associated lymphoproliferative disorders (LPDs). Although rituximab, a CD20 mAb, has proven effective against EBV‐associated LPDs, prolonged use of this drug could lead to resistance due to the selective expansion of CD20−cells. We have previously shown that cyclin‐dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins; however, the therapeutic effect of CDK inhibitors against EBV‐associated LPDs is not clear. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with alsterpaullone, an inhibitor of the CDK2 complex, resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1cell cycle arrest and apoptosis in EBV‐positive B cells. These results suggest that alsterpaullone suppresses cell cycle progression, resulting in the antitumor effect observed in vivo.