Role of E2F1 in eugenol-mediated antiproliferative activity in melanoma cells

E2F1 在丁子香酚介导的黑色素瘤细胞抗增殖活性中的作用

基本信息

批准号：
7531275
负责人：
Rita Ghosh
金额：
$ 19.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7531275
关键词：
Animals Apoptosis Base Excision Repairs Biochemical Biological Biometry Cell Cycle Cell Cycle Progression Cell Line Cell physiology Cells Clinical Clinical Trials Core Facility Cyclins DNA Damage DNA Repair Data Death Rate Development Disease Dose Down-Regulation E2F Transcription Factor 1 E2F1 gene Enrollment Eugenol Gene Expression Gene Targeting Genes Genetic Transcription Genomics Goals Growth Human Human Resources In Vitro Laboratories Lead Life Maximum Tolerated Dose Mediating Medical Informatics Melanoma Cell Metastatic Melanoma Methods Microarray Analysis Modality Molecular NCI-Designated Cancer Center Neoplasm Metastasis Neoplasms PCNA gene Pathway interactions Patient Care Patients Personal Satisfaction Phase Population Pre-Clinical Model Protein Overexpression Proteins Public Health Publishing Regulator Genes Role Route San Antonio Cancer Institute Signal Pathway Signal Transduction Spices Staging Standards of Weights and Measures Survival Rate Testing Therapeutic Therapeutic Agents Toxic effect Western Blotting Work Xenograft Model Xenograft procedure base gene repair in vivo innovation melanoma member oxidative DNA damage prevent repaired response

项目摘要

DESCRIPTION (provided by applicant): There is no effective standard therapy for patients with advanced metastatic melanoma. We have shown that eugenol, is an anti-melanoma agent in vitro and in vivo. The aim of this exploratory proposal is to establish proof of principle that (i) the safest and most effective dose of eugenol will depend on the route through which it is dispensed and (ii) E2F1 is a eugenol target in melanoma cells. Our working hypothesis is that there is a biphasic response to eugenol-induced DNA damage in melanoma cells. We have proposed that following eugenol treatment DNA damage signaling occurs through ATM/chk2 pathway that leads to stabilization of E2F1. Further there is temporal separation of E2F1 responses to eugenol as a function of DNA damage. As an immediate response E2F1 transactivates ogg1 to repair DNA base damage caused by eugenol. However as DNA damage persists E2F1 transcription activity is inhibited. As a result expression of PCNA, an E2F1 target gene does not occur and consequently cells are arrested in S phase. We will also determine the most efficacious method to deliver eugenol using the 1205Lu xenograft model. In this aim we will also determine the safest (non-toxic) eugenol dose. Results of this exploratory proposal will determine whether eugenol can be developed further as an anti-melanoma agent. Significance of this proposal is that eugenol targets a deregulated pathway in melanoma and because E2F1 regulates several genes involved in cellular processes such as apoptosis and metastasis eugenol can impact these pathways. There are no therapeutic agents in the immediate pipeline for advanced melanoma. Completion of the goals of this study will lead to subsequent proposals (RO1) aimed at obtaining a better understanding of the mechanism of action of eugenol and its clinical utility in preclinical models of melanoma. PUBLIC HEALTH RELEVANCE: Due to the lack of effective treatment options for metastatic malignant melanoma death rate continues to climb. The goal of the current proposal is to determine the most effective way to administer the compound and understand the mechanism of its growth inhibition activity. Completion of this project will take us closer to developing strategies to prevent fatal metastatic melanoma.

描述（由申请人提供）：对于晚期转移性黑色素瘤患者尚无有效的标准疗法。我们已经证明丁子香酚是体外和体内的抗黑色素瘤剂。该探索性提案的目的是建立原理证明：(i) 最安全、最有效的丁子香酚剂量将取决于其分配途径；(ii) E2F1 是黑色素瘤细胞中的丁子香酚靶点。我们的工作假设是，黑色素瘤细胞对丁子香酚诱导的 DNA 损伤存在双相反应。我们提出，丁子香酚处理后，DNA 损伤信号通过 ATM/chk2 途径发生，从而导致 E2F1 稳定。此外，作为 DNA 损伤的函数，E2F1 对丁子香酚的反应存在时间分离。作为立即反应，E2F1 反式激活 ogg1 以修复丁子香酚引起的 DNA 碱基损伤。然而，随着 DNA 损伤持续存在，E2F1 转录活性受到抑制。由于 PCNA 的表达，E2F1 靶基因不会出现，因此细胞停滞在 S 期。我们还将确定使用 1205Lu 异种移植模型传递丁子香酚的最有效方法。为此，我们还将确定最安全（无毒）的丁子香酚剂量。这一探索性提案的结果将决定丁子香酚是否可以进一步开发为抗黑色素瘤药物。该提议的意义在于，丁子香酚针对黑色素瘤中失调的通路，并且由于 E2F1 调节参与细胞过程（例如细胞凋亡和转移）的多个基因，因此丁子香酚可以影响这些通路。目前还没有针对晚期黑色素瘤的治疗药物。本研究目标的完成将产生后续提案（RO1），旨在更好地了解丁子香酚的作用机制及其在黑色素瘤临床前模型中的临床用途。公共卫生相关性：由于缺乏有效的治疗方案，转移性恶性黑色素瘤死亡率持续攀升。当前提案的目标是确定施用该化合物的最有效方法并了解其生长抑制活性的机制。该项目的完成将使我们更接近制定预防致命性转移性黑色素瘤的策略。