The role of Cdk5 as target in hepatocellular carcinoma

Cdk5作为靶标在肝细胞癌中的作用

• 批准号: 224507567
• 负责人: Professorin Dr. Angelika Vollmar
• 金额: --
• 依托单位: Department Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/224507567?language=en
• 关键词: role; Cdk5; target; hepatocellular; carcinoma

Cyclin dependent kinase 5 (Cdk5), which is not directly involved in cell cycle control, has emerged as a crucial regulator in the developing nervous system. Recently, solitary studies suggested a role of Cdk5 in tumor cell survival as well as in angiogenesis. In fact, based on our preliminary data we propose Cdk5 as an attractive target for HCC systemic therapy and anti-angiogenic approach. So far, we have shown that Cdk5 as well as p35 are upregulated in human HCC. Pharmacological or genetic inhibition of Cdk5 inhibits HCC survival, sensitizes HCC for TRAIL induced apoptosis and abrogates migration in vitro. Cdk5-inhibition reduces tumor growth and vascularization in vivo. We now aim at a detailed characterization of the molecular basis of 1) the role of Cdk5 for growth and survival of HCC cells as well as the chemosensitizing effects via inhibition of Cdk5 and 2) the impact of Cdk5 on the motility of HCC cells as well as on angiogenesis in HCC. Besides roscovitine (Seliciclib®) which has already been used in clinical phase IIb trials, we have access to novel inhibitors of Cdk5. Thus this project aims to have a translational, therapeutically relevant outcome in addition to the basic cell biological gain of knowledge.

细胞周期蛋白依赖性激酶5（Cdk 5），这是不直接参与细胞周期的控制，已成为一个重要的调节器在发育中的神经系统。最近，孤立的研究表明，Cdk 5在肿瘤细胞的生存以及在血管生成中的作用。事实上，基于我们的初步数据，我们提出Cdk 5作为HCC系统治疗和抗血管生成方法的有吸引力的靶点。到目前为止，我们已经表明Cdk 5以及p35在人HCC中上调。Cdk 5的药理学或遗传学抑制抑制HCC存活，使HCC对TRAIL诱导的细胞凋亡敏感，并在体外消除迁移。cdk 5抑制减少体内肿瘤生长和血管形成。我们现在的目标是详细表征以下分子基础：1）Cdk 5对肝癌细胞生长和生存的作用以及通过抑制Cdk 5产生的化学增敏作用; 2）Cdk 5对肝癌细胞运动性的影响以及对肝癌血管生成的影响。除了已经用于临床IIb期试验的roscovitine（Seliciclib®）外，我们还可以获得新型Cdk 5抑制剂。因此，该项目的目的是除了获得基本的细胞生物学知识之外，还具有翻译的、治疗相关的结果。

项目成果

Anti‐angiogenic effects of novel cyclin‐dependent kinase inhibitors with a pyrazolo[4,3‐d]pyrimidine scaffold

新型细胞周期蛋白依赖性激酶抑制剂与吡唑并[4,3ad]嘧啶支架的抗血管生成作用

• DOI: 10.1111/bph.13546
• 发表时间: 2016
• 期刊: British Journal of Pharmacology
• 影响因子: 7.3
• 作者: Zhang S;Ulrich M;Gromnicka A;Havlíček L;Kryštof V;Jorda R;Strnad M;Vollmar AM;Zahler S
• 通讯作者: Zahler S