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

• 批准号: 8295154
• 负责人: David Wald
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/8295154
• 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

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. PUBLIC HEALTH RELEVANCE: Most existing chemotherapeutic agents suffer from excessive toxicities. The development and understanding of novel agents that exhibit more selectivity in killing cancer cells is highly desirable. These studies aim to assess the clinical potential and mechanisms of a plant derived product that is able to preferentially target colon cancer cells.

描述（由申请人提供）：癌症治疗的主要挑战之一是由于其非选择性活性而导致化学治疗药的过度毒性。优先针对癌细胞的一种策略是利用优先杀死缺乏p53的细胞的药物，我们最近确定了一种植物来源的生物碱，该生物碱主要用于神经系统疾病，在没有p53的情况下可以优先诱导结肠癌细胞中的死亡。该化合物通过诱导p53家族成员p73的表达来诱导p53-null细胞的细胞死亡，该p73激活了凋亡。有趣的是，在存在p53的情况下，p73不是由这种生物碱诱导的，并且细胞经历了p53依赖的细胞周期停滞，从而保护它们免受凋亡。在此提案中，我们的目的是评估1）这种天然化合物对p73的独特调节2）使用小鼠异种移植研究，该药物通过该机制诱导凋亡的机制和3）该药物对结肠癌的临床潜力。该提案不仅会提供对调节p73的新型机制的生物学见解，而且还可能导致新的现有治疗剂用于结肠癌治疗。 公共卫生相关性：大多数现有的化学治疗剂都遭受过度毒性。非常需要对新型药物的发展和理解在杀死癌细胞方面具有更高的选择性。这些研究旨在评估能够优先针对结肠癌细胞的植物衍生产物的临床潜力和机制。