Mechanisms of preferential targeting of colon cancer by a plant-derived alkaloid

植物源生物碱优先靶向结肠癌的机制

基本信息

批准号：
8651428
负责人：
David Wald
金额：
$ 38.07万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651428
关键词：
Address Adverse effects Alkaloids Animals Apoptosis Apoptotic Biological Biological Models Cell Cycle Arrest Cell Death Cells Cessation of life Clinical Clinical Medicine Colon Carcinoma DNA Damage Data Development Disease Drug Kinetics Exhibits Family member Fluorouracil Goals Lead Left Malignant Neoplasms Mediating Mus Mutate Non-Malignant Normal Cell Null Lymphocytes Pathway interactions Patients Plants Property Regulation Signal Pathway Signal Transduction Stereoisomer Testing Therapeutic Therapeutic Agents Toxic effect Up-Regulation Xenograft procedure analog cancer cell cancer therapy cell killing chemotherapeutic agent colon cancer cell line experience in vivo insight killings mouse model mutant neoplastic cell nervous system disorder novel novel strategies pro-apoptotic protein protein p73 response therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): One of the main challenges in cancer therapy is the excessive toxicity of chemotherapeutics due to their nonselective activity. One strategy to preferentially target cancer cells is to utilize agents that preferentially kill cells lacking p53.We have recently identified a plant-derived alkaloid that has seen clinical use primarily for neurological disorders that can preferentially induce death in colon cancer cells in the absence of p53. This compound induces cell death in p53-null cells by inducing the expression of a p53 family member, p73, which activates apoptosis. Interestingly, in the presence of p53, p73 is not induced by this alkaloid and cells undergo a p53- dependent cell cycle arrest that protects them from apoptosis. In this proposal we aim to assess 1) the unique regulation of p73 by this natural compound 2) mechanisms through which this agent induces apoptosis and 3) the clinical potential of this agent for colon cancer using mouse xenograft studies. Not only will this proposal provide biological insights into novel mechanisms that modulate p73 but it may also lead to a new use of an existing therapeutic agent for colon cancer therapy.

描述（由申请人提供）：癌症治疗的主要挑战之一是化疗药物由于其非选择性活性而具有过度毒性。优先靶向癌细胞的一种策略是利用优先杀死缺乏 p53 的细胞的药物。我们最近发现了一种植物来源的生物碱，其临床主要用于治疗神经系统疾病，在缺乏 p53 的情况下可以优先诱导结肠癌细胞死亡。该化合物通过诱导 p53 家族成员 p73 的表达来诱导 p53 缺失细胞的细胞死亡，p73 可激活细胞凋亡。有趣的是，在 p53 存在的情况下，p73 不会被这种生物碱诱导，并且细胞会经历 p53 依赖性细胞周期停滞，从而保护它们免于凋亡。在本提案中，我们的目标是通过小鼠异种移植研究评估 1) 这种天然化合物对 p73 的独特调节 2) 该药物诱导细胞凋亡的机制以及 3) 该药物治疗结肠癌的临床潜力。该提议不仅将为调节 p73 的新机制提供生物学见解，而且还可能导致现有治疗剂在结肠癌治疗中的新用途。