Growth suppression and mitotic defect induced by JNJ-7706621, an inhibitor of cyclin-dependent kinases and aurora kinases.
Growth suppression and mitotic defect induced by JNJ-7706621, an inhibitor of cyclin-dependent kinases and aurora kinases.
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DOI：
10.2174/156800912801784839
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发表时间：
2012-06
影响因子：
3
通讯作者：
A. Matsuhashi;T. Ohno;M. Kimura;A. Hara;M. Saio;A. Nagano;G. Kawai;M. Saitou;I. Takigami;K. Yamada;Y. Okano;K. Shimizu
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文献类型：
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作者：
A. Matsuhashi;T. Ohno;M. Kimura;A. Hara;M. Saio;A. Nagano;G. Kawai;M. Saitou;I. Takigami;K. Yamada;Y. Okano;K. Shimizu
极光激酶和细胞周期蛋白依赖性激酶在细胞周期中起关键作用，并且在多种肿瘤中经常过表达，已被认为是癌症治疗的有吸引力的靶点。JNJ-7706621是最近发现的这些激酶的双重抑制剂，据报告可诱导细胞周期停滞、核内复制和细胞凋亡。在本研究中，我们进一步研究了这些影响的分子机制。抑制剂在低浓度时将多种细胞阻滞于G2期，在高浓度时阻滞于G1和G2期。JNJ-7706621未阻止Aurora A定位于纺锤体极，但在有丝分裂早期抑制其他中心体蛋白，如TOG、Nek 2和TACC 3。类似地，该药物并不阻止Aurora B定位于动粒，但确实抑制其他染色体乘客蛋白，如Survivin和INCENP。在诺考达唑释放后暴露于JNJ-7706621的细胞中，Aurora B、INCENP和Survivin重新定位至染色体的外周区域，但Plk 1和Prc 1在有丝分裂后期定位于微管上。用JNJ-7706621处理诺考达唑同步化细胞能够通过阻止纺锤体检查点信号传导来覆盖有丝分裂阻滞，导致染色体对齐和分离失败。注射该药可通过细胞周期阻滞和细胞凋亡，显著抑制裸鼠移植瘤生长。JNJ-7706621是一种在多个点调节细胞周期进程的独特抑制剂，表明其可用于细胞周期分析和各种癌症（包括尤文肉瘤）的治疗。
Aurora kinases and cyclin-dependent kinases, which play critical roles in the cell cycle and are frequently overexpressed in a variety of tumors, have been suggested as attractive targets for cancer therapy. JNJ-7706621, a recently identified dual inhibitor of these kinases, is reported to induce cell cycle arrest, endoreduplication, and apoptosis. In the present study, we further investigated the molecular mechanisms underlying these effects. The inhibitor arrested various cells at G2 phase at low concentration, and at both G1 and G2 phases at high concentration. JNJ-7706621 did not prevent localization of Aurora A to the spindle poles, but did inhibit other centrosomal proteins such as TOG, Nek2, and TACC3 in early mitotic phase. Similarly, the drug did not prevent localization of Aurora B to the kinetochore, but did inhibit other chromosomal passenger proteins such as Survivin and INCENP. In the cells exposed to JNJ-7706621 after nocodazole release, Aurora B, INCENP, and Survivin became relocated to the peripheral region of chromosomes, but Plk1 and Prc1 were localized on microtubules in later mitotic phase. Treatment of nocodazole-synchronized cells with JNJ-7706621 was able to override mitotic arrest by preventing spindle checkpoint signaling, resulting in failure of chromosome alignment and segregation. Injection of the drug significantly inhibited the growth of TC135 Ewing's sarcoma cells transplanted into athymic mice by cell cycle arrest and apoptosis. JNJ-7706621 is a unique inhibitor regulating cell cycle progression at multiple points, suggesting that it could be useful for cell cycle analysis and therapy of various cancers, including Ewing's sarcoma.