Dihydromethysticin (DHM) for Lung Cancer Chemoprevention

二氢迷幻素 (DHM) 用于肺癌化学预防

• 批准号: 9070717
• 负责人: CHENGGUO XING
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070717
• 关键词: A/J Mouse; Adverse effects; Aryl Hydrocarbon Receptor; Award; Cancer Etiology; Carcinogen exposure; Carcinogens; Cause of Death; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Management; DNA Adduction; DNA Adducts; DNA Modification Process; Data; Development; Diet; Disease; Dose; Drug Metabolic Detoxication; Future; Grant; Hand; Health; Human; Inbred F344 Rats; Investigational New Drug Application; Kava; Knowledge; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Metabolism; Modeling; Mus; Natural Products; Oncogenic; Pathway interactions; Plant Roots; Positioning Attribute; Preparation; Prevention; Prevention strategy; Public Health; Rattus; Reporting; Risk; Role; Safety; Smoker; Solid; Specificity; Structure of parenchyma of lung; Surrogate Markers; Testing; Time; Tobacco; Tobacco Use Cessation; Tobacco-Associated Carcinogen; Toxicology; Translations; Urine; War; analog; base; cancer chemoprevention; cancer initiation; cancer risk; carcinogenesis; cigarette smoking; functional group; good laboratory practice; in vivo; lung cancer prevention; lung tumorigenesis; novel; preclinical study; prevent; research clinical testing; translational study; tumor initiation

 DESCRIPTION (provided by applicant): Lung cancer causes ~160,000 deaths annually in the U.S. and prevention will be crucial to win the war on this deadliest cancer. Since DNA modification by tobacco carcinogens is one major driver for lung cancer initiation, blocking DNA adduct formation (the root cause) is a plausible strategy. This proposal focuses on the preclinical studies of dihydromethysticin (DHM) as a novel and highly efficacious chemopreventive agent that inhibits lung tumor initiation via preventing tobacco carcinogen-induced DNA modification. Preliminary data demonstrate that DHM (given during carcinogen exposure period at a dose of 50 ppm in diet) completely blocked NNK-induced lung tumor formation in A/J mice. A natural analog, dihydrokavain (DHK), was completely inactive even at 500 ppm in diet. Such a sharp in vivo difference suggests a crucial role of methylenedioxy functional group for specific targeting by DHM. DHM selectively reduced NNAL (the active metabolite of NNK)-induced DNA adducts in the lung tissues. DHM also reduced NNK-derived DNA adducts in F344 rats, indicating its cross-species anti-initiation potential. Based on the reported activity of DHM in activating aryl hydrocarbon receptor (AHR) and our own data of DHM in increasing glucuronidated NNAL in mouse urine, we propose that DHM activates detoxification pathways as the primary mechanism of action. With respect to safety, 17-week dietary exposure of DHM to A/J mice caused no adverse effects at 500 ppm, affording a wide safety margin as a lung cancer chemopreventive agent for long-term use. Our central hypothesis is that DHM effectively prevents tobacco carcinogen-induced lung tumorigenesis, at least in major part, by enhancing carcinogen detoxification potentially via activating AHR leading to a reduction in oncogenic DNA adducts in the target lung tissues. This hypothesis will be tested by accomplishing the following aims: Aim 1 To elucidate the structural determinant(s) of DHM (i.e., intact DHM or its metabolite) for its exceptional in vivo inhibitory activities against NNK-induced DNA adduct formation and lung tumor initiation. Data will also inform the in vivo active form of DHM. Aim 2 To investigate enhanced detoxification as a key mechanism of DHM to inhibit NNK-induced DNA adduct formation and lung tumor initiation. Data will also inform its potential to protect against other tobacco carcinogens and identify surrogate biomarkers for future translational studies. Aim 3 To evaluate the efficacy of DHM against NNK-induced lung tumorigenesis in F344 rats and BaP-induced lung tumorigenesis in A/J mice. Data will inform its cross-species applicability and carcinogen specificity. If the results support our hypothesis, DHM will be well positioned for Good Laboratory Practice (GLP)-based toxicology in higher mammals in preparation for an IND application for human translation studies. The mechanistic knowledge will not only identify surrogate biomarkers critical for translation, but also advance our basic understanding about NNAL metabolism and carcinogenesis.

 描述（应用程序提供）：肺癌每年在美国造成约160,000人死亡，预防对于赢得这场最致命的癌症的战争至关重要。由于烟草致癌物的DNA修饰是肺癌启动的主要驱动力之一，因此阻断DNA加合物形成（根本原因）是一个合理的策略。该建议的重点是二氢甲基固醇（DHM）作为一种新型且高效的化学预防剂的临床前研究，该剂通过防止烟草致癌物诱导的DNA修饰来抑制肺部肿瘤感染。初步数据表明，DHM（在饮食中以50 ppm的剂量在致癌物暴露期间给予）完全阻断了A/J小鼠中NNK诱导的肺肿瘤形成。天然的类似物，二氢kavain（DHK），即使在饮食中以500 ppm的速度也是完全无活跃的。如此急剧的体内差异表明，甲基二氧官能团在DHM的特定靶向方面起着至关重要的作用。 DHM有选择地降低NNAL（NNK的活性代谢产物）诱导的DNA加合物。 DHM还降低了F344大鼠中NNK衍生的DNA加合物，表明其跨物种抗发射潜力。基于DHM在激活芳烃受体（AHR）中报道的活性，以及​​我们自己对小鼠尿液中谷氨酸NNAL的DHM数据的数据，我们建议DHM激活解毒途径作为作用的主要机制。在安全性方面，DHM向A/J小鼠的饮食暴露17周，在500 ppm时不会引起不良影响，作为长期使用的肺癌化学预防剂，可提供广泛的安全水平。我们的中心假设是，DHM至少在主要部分有效地防止了烟草致癌物诱导的肺肿瘤发生，从而通过激活AHR来增强致癌物解毒，从而减少靶肺组织中的致癌DNA加合物。该假设将通过完成以下目的来检验：目的1阐明DHM的结构确定剂（即完整的DHM或其代谢物），以针对NNK诱导的DNA添加功能的特殊体内抑制活性和肺部Tumor的启动。数据还将告知DHM的体内活动形式。 AIM 2以研究增强的排毒作为DHM抑制NNK诱导的DNA加合物形成和肺部肿瘤感染的关键机制。数据还将为其防止其他烟草癌的潜力提供信息，并确定替代生物标志物以进行未来的转化研究。 AIM 3评估DHM对F344大鼠中NNK诱导的肺肿瘤发生的有效性以及A/J小鼠BAP诱导的肺肿瘤发生的有效性。数据将为其跨物种的可施用性和致癌特异性提供信息。如果结果支持我们的假设，DHM将在高级哺乳动物中基于良好的实验室实践（GLP）毒理学良好的位置，以准备为人类翻译研究的IND应用。机械知识不仅可以识别替代生物标志物对翻译至关重要，而且还可以提高我们对NNAL代谢和致癌作用的基本理解。