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

描述(申请人提供)：癌症治疗中的主要挑战之一是化疗药物因其非选择性活性而产生的过度毒性。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，它已被临床用于治疗神经疾病，在缺乏p53的情况下，这种疾病可以优先诱导结肠癌细胞死亡。这种化合物通过诱导P53家族成员p73的表达来诱导P53缺失细胞的细胞死亡，从而激活细胞凋亡。有趣的是，在P53存在的情况下，这种生物碱不会诱导p73，细胞会经历依赖于P53的细胞周期停滞，以保护它们免受凋亡。在这项建议中，我们旨在评估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，以及3)这种药物在小鼠异种移植研究中治疗结肠癌的临床潜力。这项提议不仅将为调节p73的新机制提供生物学见解，还可能导致现有治疗药物在结肠癌治疗中的新用途。

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.