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.

项目概要： 非小细胞肺癌（NSCLC）是最常见的肺癌，占所有肺癌的 85% 美国的案例。吸烟是这种疾病和戒烟者的主要原因 仍处于较高风险。大约 40% 的 NSCLC 是腺癌 (LUAD)。 LUAD 病例数 预计前吸烟者人数将会增加。对高危人群进行 LUAD 发展的化学预防，例如 戒烟是降低非小细胞肺癌死亡率的重要策略。此外，LUAD 转移至 大脑是导致死亡的主要原因之一。因此，发现新的策略来预防原发性和 转移性 LUAD 至关重要。因为接受预防性治疗的患者没有明显的症状。 疾病，这样的治疗不仅必须有效，而且副作用的风险也非常低。和厚朴 (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 在动物模型中预防多种癌症的发展。我们最近展示了强大的 HNK 在化学预防小鼠肺部肿瘤发生中的功效。 HNK作用机制分析 表明其作用主要是通过线粒体依赖性诱导细胞凋亡来介导的 机制。这为将 HNK 与靶向剂缀合提供了支持性原理，从而驱动其进入 线粒体以显着提高其化学预防功效。初步数据表明 线粒体靶向 HNK (Mito-HNK) 也是一种更有效的 LUAD 脑化学预防剂 转移（该疾病的常见临床特征）高于 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剂，主要通过新型药物发挥作用 线粒体机制。该假设将在三个具体目标上进行检验。目标 1 将评估 Mito-HNK 的体外化学预防潜力和作用机制。目标 2 将确定 Mito-HNK 对 A/J 小鼠肺肿瘤进展的化学预防功效。目标 3 将确定 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 成像技术监测原发肿瘤的生长（磁共振成像）和移植 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的产生（生物发光成像）。这将能够实现精确和准确 监测 Mito-HNK 在肿瘤发生的不同阶段的功效。开发一种药物的临床影响 新型、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 该提案可用于指导未来临床试验的进程，并可能指导完整的开发 用于 LUAD 化学预防的新型药物。