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

描述（由申请人提供）：癌症治疗的主要挑战之一是化疗药物的非选择性活性导致的过度毒性。一种优先靶向癌细胞的策略是利用优先杀死缺乏p53的细胞的药物。我们最近鉴定了一种植物来源的生物碱，其主要用于神经系统疾病，可以在缺乏p53的情况下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缺失细胞中的细胞死亡，p73激活细胞凋亡。有趣的是，在p53的存在下，p73不被这种生物碱诱导，细胞经历p53依赖性细胞周期阻滞，保护它们免于凋亡。在这项提案中，我们的目的是评估1）这种天然化合物对p73的独特调节，2）这种药物诱导细胞凋亡的机制，3）使用小鼠异种移植研究这种药物治疗结肠癌的临床潜力。这一提议不仅将为调节p73的新机制提供生物学见解，而且还可能导致现有治疗剂用于结肠癌治疗的新用途。

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.