Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol

利用线粒体靶向和厚朴酚化学预防肺癌

基本信息

批准号：
10497449
负责人：
BALARAMAN KALYANARAMAN
金额：
$ 52.37万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10497449
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

项目摘要

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% 在美国，吸烟是这种疾病的主要原因，而且吸烟者也是如此。大约 40% 的 NSCLC 是腺癌 (LUAD)，其中 LUAD 病例的数量仍然较高。预计前吸烟者在高危人群（如）中对 LUAD 发展的化学预防将会增加。此外，戒烟者是降低 NSCLC 死亡率的重要策略。大脑是死亡的主要原因之一，因此，寻找新的策略来预防原发性和死亡。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，而且副作用的风险非常低，木兰树皮提取物中存在的天然化合物，具有良好的安全性，并已被证明我们最近在动物模型中证明了其有效预防多种癌症的发展。 HNK对小鼠肺部肿瘤发生的化学预防作用分析HNK的作用机制。表明其作用主要是通过线粒体依赖性诱导细胞凋亡来介导的这为将 HNK 与驱动其进入的靶向剂结合提供了支持性原理。线粒体以显着提高其化学预防功效。线粒体靶向 HNK (Mito-HNK) 也是一种更有效的 LUAD 脑化学预防剂我们发现 Mito-HNK 是一种新型的、 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该假设将在三个具体目标中进行测试。 Mito-HNK 的体外化学预防潜力和作用机制将决定 Aim 2。 Mito-HNK 对 A/J 小鼠肺部肿瘤进展的化学预防功效将决定 Aim 3。 Mito-HNK 对 LUAD 脑转移的化学预防功效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）这将实现精确和准确。监测 Mito-HNK 在肿瘤发生的不同阶段的功效。新型、有效的 LUAD 化学预防药物将具有非常重要的意义。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。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detection of mitochondria-generated reactive oxygen species in cells using multiple probes and methods: Potentials, pitfalls, and the future.

使用多种探针和方法检测细胞中线粒体产生的活性氧：潜力、陷阱和未来。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Cheng, Gang;Zielonka, Monika;Dranka, Brian;Kumar, Suresh N;Myers, Charles R;Bennett, Brian;Garces, Alexander M;Dias Duarte Machado, Luiz Gabriel;Thiebaut, David;Ouari, Olivier;Hardy, Micael;Zielonka, Jacek;Kalyanaraman, Balaraman
通讯作者：
Kalyanaraman, Balaraman

Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity.

靶向线粒体的和厚朴酚通过抑制复合物 I 活性对肺癌具有显着的抑制作用。

DOI：
发表时间：
2018-05-25
期刊：
影响因子：
5.8
作者：
Pan, Jing;Lee, Yongik;Cheng, Gang;Zielonka, Jacek;Zhang, Qi;Bajzikova, Martina;Xiong, Donghai;Tsaih, Shirng;Hardy, Micael;Flister, Michael;Olsen, Christopher M;Wang, Yian;Vang, Ole;Neuzil, Jiri;Myers, Charles R;Kalyanaraman, Balaraman
通讯作者：
Kalyanaraman, Balaraman

Tumor intrinsic immunity related proteins may be novel tumor suppressors in some types of cancer.

肿瘤内在免疫相关蛋白可能是某些类型癌症中的新型肿瘤抑制因子。