A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer.
A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer.
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DOI：
10.1371/journal.pone.0012417
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发表时间：
2010-09-14
期刊：
影响因子：
3.7
通讯作者：
Wang YC
中科院分区：
文献类型：
--
作者：
Tang YA;Wen WL;Chang JW;Wei TT;Tan YH;Salunke S;Chen CT;Chen CS;Wang YC
肺癌是世界范围内癌症死亡的主要原因，但晚期非小细胞肺癌（NSCLC）的治疗策略效果有限。此外，用于治疗实体瘤的经验证的组蛋白脱乙酰酶（HDAC）抑制剂仍有待开发。在这里，我们提出了一种新的HDAC抑制剂，OSU-HDAC-44，作为NSCLC的化疗药物。在包括A549（p53野生型）、H1299（p53无效）和CL 1 -1（p53突变体）的三种人NSCLC细胞系中检查OSU-HDAC-44的细胞毒性作用。通过流式细胞仪细胞周期分析、细胞凋亡分析和全基因组染色质免疫沉淀芯片（ChIP-on-chip）分析，研究OSU-HDAC-44的抗增殖机制。用OSU-HDAC-44或载体对照处理具有已建立的A549肿瘤异种移植物的小鼠，并用于评估对肿瘤生长、胞质分裂抑制和细胞凋亡的影响。OSU-HDAC-44是一种泛HDAC抑制剂，在抑制各种NSCLC细胞系中的细胞活力方面表现出比辛二酰苯胺异羟肟酸（SAHA）高3-4倍的有效性。在OSU-HDAC-44处理后，胞质分裂被抑制，随后导致细胞凋亡。胞质分裂抑制是由OSU-HDAC-44介导的有丝分裂和胞质分裂调节因子Auroroa B和survivin的降解引起的。由OSU-HDAC-44诱导的F-肌动蛋白动力学的失调与由srGAP 1诱导引起的RhoA活性的降低相关。ChIP芯片分析显示，OSU-HDAC-44诱导染色质松动，并促进参与细胞凋亡、轴突导向和蛋白泛素化等关键信号通路的基因转录。最后，OSU-HDAC-44在体内有效地抑制A549异种移植肿瘤生长并诱导组蛋白和非组蛋白蛋白的乙酰化和细胞凋亡。OSU-HDAC-44在NSCLC临床前模型中通过诱导胞质分裂缺陷和内在凋亡显著抑制肿瘤生长。我们的数据提供了令人信服的证据，证明OSU-HDAC-44是一种有效的HDAC靶向抑制剂，可以用于NSCLC化疗。
Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferatative mechanisms of OSU-HDAC-44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3–4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy.
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影响因子：
4.8
作者：
Tang, TTL;Dowbenko, D;Lasky, LA
通讯作者：
Lasky, LA
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158.5
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