Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol

项目总结： 非小细胞肺癌是最常见的肺癌，占所有肺癌的85% 在美国的案例。吸烟是这种疾病的主要原因，以前吸烟者 仍处于高风险状态。大约40%的非小细胞肺癌是腺癌(LUAD)。年LUAD病例数量 预计以前的吸烟者将会增加。高危人群LUAD发展的化学预防，如 戒烟者是降低非小细胞肺癌死亡率的重要策略。此外，LUAD的转移到 大脑是导致死亡的主要原因之一。因此，发现新的战略来预防初级和 转移性LUAD至关重要。因为将接受预防性治疗的患者没有明显的 如果你不想患上这种疾病，这种治疗方法不仅必须有效，而且副作用的风险也必须非常低。和厚朴酚(HNK)、 厚朴树皮提取物中的一种天然化合物，具有良好的安全性，已被证明 在动物模型中预防几种类型的癌症的发展。我们最近证明了它的威力 HNK对小鼠肺肿瘤的化学预防作用。HNK的作用机制分析 提示它的作用主要是通过线粒体依赖诱导细胞凋亡来实现的。 机制。这为将HNK与靶向试剂结合提供了一个支持性的理论基础，该靶向试剂可推动HNK进入 线粒体，以显著提高其化学预防效果。初步数据显示， 线粒体靶向HNK(Mito-HNK)也是LUAD脑的一种更有效的化学预防药物 转移(该病的常见临床特征)多于HNK。我们假设Mito-HNK是一部小说， LUAD进展和转移的有效化学预防药物，主要通过新型药物发挥作用 线粒体机制。这一假设将在三个具体目标上得到检验。目标1将评估 Mito-HNK的体外化学预防作用及其机制。目标2将决定 Mito-HNK对A/J小鼠肺癌进展的化学预防作用目标3将决定 Mito-HNK对LUAD脑转移的化学预防作用我们将使用最先进的小动物 监测原发肿瘤生长的成像技术(磁共振成像)和植入术 转移细胞以及体内监测癌细胞变化的创新方法 生物能量学和细胞氧化剂生产(生物发光成像)。这将使精确和准确成为可能 监测Mito-HNK在肿瘤形成不同阶段的疗效。发展一种新技术对临床的影响 新的、有效的LUAD化学预防药物将具有非常重要的意义。由此产生的知识 建议可用于指导未来临床试验的进程，并可指导完全 用于LUAD化学预防的新型试剂。

Project Summary: Non-small-cell lung cancers (NSCLCs) are the most common lung cancers, accounting for 85% of all lung cancer cases in the United States. Cigarette smoking is the predominant cause of this disease and former smokers remain at elevated risk. About 40% of NSCLCs are adenocarcinomas (LUAD). The number of LUAD cases in former smokers is expected to rise. Chemoprevention of LUAD development in at-risk populations such as former smokers is an important strategy to reduce NSCLCs mortality. Furthermore, metastasis of LUAD to the brain is one of the leading causes of mortality. Thus, discovering new strategies to prevent primary and metastatic LUAD is critically important. Because patients who will receive preventive treatment do not have overt disease, such treatments must not only be effective but also have a very low risk of side effects. Honokiol (HNK), a natural compound present in magnolia bark extracts, has a favorable safety profile and has been shown to prevent the development of several types of cancer in animal models. We have recently demonstrated potent efficacy of HNK in the chemoprevention of lung tumorigenesis in mice. Analysis of HNK’s mechanism of action suggests that its effect is primarily mediated by inducing apoptosis through a mitochondria-dependent mechanism. This provides a supportive rationale for conjugating HNK to a targeting agent that drives it into mitochondria in order to dramatically increase its chemopreventive efficacy. Preliminary data demonstrate that mitochondria-targeted HNK (Mito-HNK) is also a significantly more potent chemopreventive agent of LUAD brain metastasis (a common clinical feature of the disease) than HNK. We hypothesize that Mito-HNK is a novel, potent chemopreventive agent of LUAD progression and metastasis and acts primarily through novel mitochondrial mechanisms. This hypothesis will be tested in three specific aims. Aim 1 will evaluate the chemopreventive potential and mechanisms of action of Mito-HNK in vitro. Aim 2 will determine the chemopreventive efficacy of Mito-HNK on lung tumor progression in A/J mice. Aim 3 will determine the chemopreventive efficacy of Mito-HNK on LUAD brain metastasis. We will use state-of-the-art small animal imaging technology to monitor the growth of primary tumors (magnetic resonance imaging) and engraftment of metastatic cells as well as innovative approaches for in vivo monitoring of the changes in cancer cell bioenergetics and cellular oxidant production (bioluminescent imaging). This will enable precise and accurate monitoring of the efficacy of Mito-HNK in distinct stages of tumorigenesis. The clinical impact of developing a novel, potent agent for LUAD chemoprevention will be highly significant. The knowledge generated from this proposal could be used to direct the course of future clinical trials and may guide the development of an entirely new class of agents for LUAD chemoprevention.