Chemoprevention of lung cancer with mitochondria-targeted honokiol

线粒体靶向和厚朴酚对肺癌的化学预防

• 批准号: 10092125
• 负责人: BALARAMAN KALYANARAMAN
• 金额: $ 11.51万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092125
• 关键词: A/J Mouse; Accounting; Adenocarcinoma; Adenocarcinoma Cell; Animal Model; Apoptosis; Asians; Biochemical; Bioenergetics; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Complex; Data; Development; Disease; Dose; Electron Spin Resonance Spectroscopy; Engraftment; Foundations; Future; Generations; Growth; Human; Image; Imaging technology; In Vitro; Individual; Injections; Knowledge; Laboratories; Left ventricular structure; Lung; Lung Adenocarcinoma; Lung Neoplasms; Magnetic Resonance Imaging; Magnolia; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medicine; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Mitochondria; Monitor; Mus; NADH dehydrogenase (ubiquinone); NOD/SCID mouse; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oxidants; Oxidation-Reduction; Oxygen Consumption; Parents; Patients; Pattern; Phosphorylation; Populations at Risk; Preventive treatment; Primary Brain Neoplasms; Primary Neoplasm; Production; Property; Reactive Oxygen Species; Reporting; Research; Respiration; Risk; Role; STAT3 gene; Safety; Signal Pathway; Signal Transduction; Structure; System; Testing; Time; Ultrasonography; United States; analog; animal imaging; base; cancer cell; cancer type; cell growth; cigarette smoking; cold temperature; design; disorder control; efficacy evaluation; former smoker; honokiol; in vivo; in vivo Model; in vivo imaging; in vivo monitoring; innovation; insight; luminescence; lung tumorigenesis; migration; mortality; mouse model; neoplastic cell; novel; oxidation; peroxiredoxin; premalignant; prevent; response; side effect; targeted agent; tumor; tumor progression; tumorigenesis

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.

项目摘要： 非小细胞肺癌（NSCLC）是最常见的肺癌，占所有肺癌的85％ 在美国。吸烟是这种疾病的主要原因和前吸烟者 保持风险较高。大约40％的NSCLC是腺癌（LUAD）。 LUAD案件的数量 预计前吸烟者将上升。在高危人群中的LUAD发展的化学预防 前吸烟者是降低NSCLC死亡率的重要策略。此外，Luad转移到 大脑是死亡率的主要原因之一。这是发现防止主要和的新策略 转移性LUAD至关重要。因为将接受预防治疗的患者没有明显 疾病，这种治疗不仅必须有效，还必须具有非常低的副作用风险。 Honokiol（HNK）， 木兰树皮提取物中存在的天然化合物具有良好的安全性，并已被证明是 防止动物模型中几种类型的癌症的发展。我们最近证明了有力的 HNK在小鼠肺肿瘤发生化学预防中的功效。分析HNK的作用机制 表明其作用主要是通过线粒体依赖性诱导的凋亡介导的 机制。这为将HNK连接到靶向代理提供了支持的理由 线粒体为了显着提高其化学预防效率。初步数据表明 线粒体靶向的HNK（Mito-HNK）也是Luad脑的潜在化学预防剂 转移（疾病的常见临床特征）比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剂，并通过新型作用 线粒体机制。该假设将以三个特定目的进行检验。 AIM 1将评估 Mito-HNK体外的化学预防潜力和作用机理。 AIM 2将确定 MITO-HNK对A/J小鼠肺肿瘤进展的化学预防效率。 AIM 3将确定 MITO-HNK在LUAD脑转移上的化学预防效率。我们将使用最先进的小动物 成像技术以监测原发性肿瘤的生长（磁共振成像）和植入 转移细胞以及用于体内监测癌细胞变化的创新方法 生物能和细胞氧化物产生（生物发光成像）。这将使精确和准确 在肿瘤发生的不同阶段，监测Mito-HNK的效率。开发临床影响 新型LUAD化学预防的潜在药物将非常重要。从中产生的知识 建议可以用于指导未来的临床试验过程，并可能指导一个完全的发展 LUAD化学预防的新产品。