K Vitamins- A New Class of Liver Cell Growth Inhibitors

K 维生素 - 一类新型肝细胞生长抑制剂

• 批准号: 6821599
• 负责人: BRIAN I CARR
• 金额: $ 26.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-08 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821599
• 关键词: antineoplastics; carboxylation; cell cycle proteins; cofactor; enzyme inhibitors; growth inhibitors; hepatocellular carcinoma; intracellular transport; laboratory rat; liver cells; neoplastic cell; phosphoprotein phosphatase; phosphoproteins; phosphorylation; protein tyrosine phosphatase; vitamin K; vitamin analog

DESCRIPTION (provided by applicant): K vitamin metabolism is dysregulated in hepatomas. We found in our first grant, that K vitamin analogs are inhibitors of hepatoma cell growth and selectively inhibit protein tyrosine phosphatases (PTPs), causing profound and prolonged ERK phosphorylation, which is essential to their growth inhibitory actions. It is now proposed to examine the mechanisms for this. Our working hypothesis is that our model analog, Cpd 5, inhibits Cdc25A (and other PTPs), causing prolonged and intense phosphorylation of selected proteins, which causes growth inhibition. In particular, ERK is phosphorylated and translocated to the nucleus. MEK inhibitors abrogate all the Cpd 5 effects. The specific aims are to examine: 1. The interactions of Cpd 5 with Cdc25A and the cellular consequences of these. 2. The significance and mechanisms of prolonged ERK phosphorylation and nuclear translocation. 3. The consequences of prolonged ERK activation for cell growth inhibition by Cpd 5 and new analogs. 4. To test the long-term in vivo effects of Cpd 5 on HCC growth and inhibition of chemical rat hepatocarcinogenesis and to evaluate the cellular and in vivo actions of some new, more potent analogs that are Cdc25 inhibitors, since Cdc25 over-expression is a feature of many tumor types. 5. The novelty of this work is (a) the finding of even more potent PTP inhibitors of an entirely new class of drug (K vitamin analogs); (b) the idea that prolonged ERK phosphorylation is an important mediator of growth inhibition (it was previously associated with growth stimulation); (c) the hypothesis, supported by data, that Cdc25 group of cell cycle regulating PTPs may control ERK phosphorylation; (d) these novel K vitamin analogs also work in vivo and likely by similar mechanisms as found in vitro and have the potential for both treating and preventing hepatoma formation in vivo.

描述（由申请人提供）：肝癌中 K 维生素代谢失调。我们在第一笔资助中发现，K 维生素类似物是肝癌细胞生长的抑制剂，并选择性抑制蛋白酪氨酸磷酸酶 (PTP)，导致 ERK 深度且持久的磷酸化，这对于其生长抑制作用至关重要。现在建议研究这方面的机制。我们的工作假设是，我们的模型类似物 Cpd 5 抑制 Cdc25A（和其他 PTP），导致所选蛋白质长时间且强烈的磷酸化，从而导致生长抑制。特别是，ERK 被磷酸化并转移至细胞核。 MEK 抑制剂消除所有 Cpd 5 的作用。 具体目标是检查： 1. Cpd 5 与 Cdc25A 的相互作用以及这些相互作用的细胞后果。 2. ERK长时间磷酸化和核转位的意义和机制。 3. Cpd 5 和新类似物延长 ERK 激活对细胞生长抑制的影响。 4. 测试 Cpd 5 对 HCC 生长和抑制化学大鼠肝癌发生的长期体内作用，并评估一些新的、更有效的 Cdc25 抑制剂类似物的细胞和体内作用，因为 Cdc25 过度表达是许多肿瘤类型的特征。 5. 这项工作的新颖之处在于 (a) 发现了一种全新药物（K 维生素类似物）的更有效的 PTP 抑制剂； (b)延长ERK磷酸化是生长抑制的重要介质的观点（之前它与生长刺激有关）； (c) 有数据支持的假设，即细胞周期调节 PTP 的 Cdc25 组可能控制 ERK 磷酸化； (d) 这些新型 K 维生素类似物也在体内发挥作用，并且可能通过与体外发现的类似机制发挥作用，并且具有在体内治疗和预防肝癌形成的潜力。