Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts.
Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts.
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DOI：
10.1158/1535-7163.mct-09-1207
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发表时间：
2010-05
影响因子：
5.7
通讯作者：
Kuppusamy P
中科院分区：
文献类型：
--
作者：
Selvendiran K;Tong L;Bratasz A;Kuppusamy ML;Ahmed S;Ravi Y;Trigg NJ;Rivera BK;Kálai T;Hideg K;Kuppusamy P
本研究的目的是评估新型二氟二芳基哌啶酮 (H-4073) 及其 N-羟基吡咯啉修饰物 (HO-3867) 对人类卵巢癌的抗癌效力和机制。使用已建立的人卵巢癌细胞系（A2870、A2780cDDP、OV-4、SKOV3、PA-1 和 OVCAR3）以及鼠异种移植肿瘤 (A2780) 模型进行研究。两种化合物对 A2780 细胞具有相当且显着的细胞毒性。然而，HO-3867 对卵巢癌细胞具有优先毒性，同时不伤害健康细胞。 HO-3867通过调节细胞周期调节分子p53、p21、p27、cdk2和细胞周期蛋白诱导A2780细胞G2/M细胞周期停滞，并通过caspase-8和caspase-3激活促进细胞凋亡。它还导致功能性 Fas/CD95 表达增加以及 STAT3 (Tyr705) 和 JAK1 磷酸化减少。 STAT3 下游靶蛋白水平显着降低，包括 Bcl-xL、Bcl-2、生存素和血管内皮生长因子 (VEGF)，表明 HO-3867 暴露破坏了 JAK/STAT3 信号通路。此外，HO-3867以剂量依赖性方式显着抑制卵巢异种移植肿瘤的生长，且没有任何明显的毒性。异种移植肿瘤组织的蛋白质印迹分析表明，HO-3867 抑制 pSTAT3（Tyr705 和 Ser727）和 JAK1，并增加凋亡标记物 caspase-3 和 PARP。 HO-3867 通过抑制 JAK/STAT3 信号通路对卵巢癌细胞表现出显着的细胞毒性。该研究表明 HO-3867 可能作为一种安全有效的抗癌药物用于卵巢癌治疗。
The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were performed using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1 and OVCAR3), as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 demonstrated a preferential toxicity towards ovarian cancer cells, while sparing healthy cells. HO-3867 induced G2/M cell-cycle arrest in A2780 cells by modulating cell-cycle regulatory molecules p53, p21, p27, cdk2 and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in STAT3 (Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor (VEGF), suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western-blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and PARP. HO-3867 exhibited significant cytotoxicity towards ovarian cancer cells by inhibition of the JAK/STAT3-signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy.