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Melatonin as a novel Sirt1 inhibitor for the management of prostate cancer

褪黑素作为一种新型 Sirt1 抑制剂用于治疗前列腺癌

基本信息

批准号：
7750811
负责人：
Brittney Jung-Hynes
金额：
$ 3.58万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2010-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750811
关键词：
Acetylation Adenocarcinoma Adjuvant Adverse effects Age Aging American American Cancer Society Animals Antioxidants Apoptosis Biological Brain Cancer Patient Cell Aging Cell Fate Control Cell Proliferation Cell Survival Cells Chemopreventive Agent Circadian Rhythms Crying Data Deacetylase Developed Countries Developing Countries Development Enrollment Epithelial Cells Experimental Models Family Genes Genetic Transcription Histone Deacetylase Histones Homologous Gene Hormones Human Human body Hypothalamic structure Immune system In Vitro LNCaP Link Longevity Malignant Neoplasms Malignant neoplasm of prostate Mediating Medicine Melatonin Messenger RNA Metabolism Minerals Modality Molecular Mus Nicotinamide adenine dinucleotide Organ Organism Patients Phase I Clinical Trials Prevention Prostate Proteins Recurrence Reporting Role Signal Transduction Sirtuins Skin Cancer Surveys Testing Tissues Toxic effect Transgenic Organisms Treatment Protocols Tumor Suppressor Proteins Vitamins Work Yeasts base cancer cell cell growth chemotherapy circadian pacemaker design human disease in vivo inhibitor/antagonist man men novel novel strategies overexpression prevent senescence sirtinol treatment effect tumor

项目摘要

DESCRIPTION (provided by applicant): Prostate Cancer (PCa) is the most commonly occurring malignancy in men in the USA and several other developed countries. A man's chance of developing PCa significantly increases with increasing age; therefore, it is important to define the causal connection between mechanisms of aging and PCa. In a recent study, we have found Sirti, a longevity-associated histone deacetylase, is overexpressed in PCa cells and tissues and its inhibition causes a decrease in cell growth and viability and increase in senescence in PCa cells. Further, our recent exciting preliminary data has shown that melatonin, a pineal hormone and a widely used supplement among cancer patients, is a potent inhibitor of Sirti. Melatonin synthesis by the human body displays a circadian rhythm that is generated by a circadian clock located in the hypothalamus. Studies have shown that melatonin possesses chemopreventive, oncostatic and tumor inhibitory effects in a variety of experimental models. Further, melatonin has a potential to increase the efficacy and decrease the side effects of chemotherapy in adjuvant settings. In vitro studies have also indicated that melatonin possesses antiproliferative effects against human PCa cells. Importantly Sirti has been found to be required for circadian transcription of several core clock genes (Bmall, Rory, Per2, and Cryl) suggesting that Sirti connects cellular metabolism to the circadian core clockwork circuitry. Melatonin has been shown to control a variety of clock genes which have recently been linked to cancer. This proposal capitalizes on these novel observations and the central hypothesis of the work proposed in this application is that melatonin will impart anti-proliferative as well as chemopreventive effects against prostate cancer via Sirti inhibition-mediated modulations in circadian core clockwork circuitry. The following specific aims are proposed; 1) To establish a cause-and-effect association between the anti-proliferative effects of melatonin and Sirti in human PCa cells; 2) To determine the involvement of circadian rhythm genes as a mechanism of the anti-proliferative effects of melatonin in PCa cells; and 3) To determine if melatonin will impart anti-proliferative and/or chemopreventive effects against PCa via Sirti inhibition-mediated modulations in clock genes in vivo in transgenic adenocarcinoma mouse prostate (TRAMP) mice, which mimics the features of human disease. We believe that successful completion of this proposal will establish i) the potential of melatonin (a widely used CAM approach) against PCa, and ii) a novel molecular mechanism(s) of the biological effects of melatonin. This may help in designing novel strategies for the management of PCa.

描述（由申请人提供）：前列腺癌（PCa）是美国和其他几个发达国家男性中最常见的恶性肿瘤。一个人的机会发展PCa显着增加与年龄的增长;因此，重要的是要确定老化和PCa的机制之间的因果关系。在最近的一项研究中，我们发现Sirti，一种长寿相关的组蛋白脱乙酰酶，在PCa细胞和组织中过表达，其抑制导致PCa细胞生长和活力下降，衰老增加。此外，我们最近令人兴奋的初步数据表明，褪黑激素，一种松果体激素和癌症患者中广泛使用的补充剂，是Sirti的有效抑制剂。人体的褪黑激素合成显示由位于下丘脑中的昼夜节律钟产生的昼夜节律。研究表明，褪黑素在多种实验模型中具有化学预防、抑瘤和肿瘤抑制作用。此外，褪黑激素具有在辅助环境中增加化疗的功效和减少化疗的副作用的潜力。体外研究还表明，褪黑激素对人前列腺癌细胞具有抗增殖作用。重要的是，已经发现Sirti是几个核心时钟基因（Bmall，Rory，Per 2和Cryl）的昼夜节律转录所需的，这表明Sirti将细胞代谢与昼夜节律核心时钟电路连接起来。褪黑激素已被证明可以控制各种生物钟基因，这些基因最近被认为与癌症有关。该提议利用了这些新的观察结果，并且在本申请中提出的工作的中心假设是褪黑激素将通过Sirti抑制介导的昼夜核心时钟电路中的调节来赋予抗增殖以及针对前列腺癌的化学预防作用。提出了以下具体目标：1）建立褪黑激素和Sirti在人PCa细胞中的抗增殖作用之间的因果关系：2）确定昼夜节律基因的参与作为褪黑激素在PCa细胞中的抗增殖作用的机制;和3）为了确定褪黑激素是否将通过Sirti抑制而赋予针对PCa的抗增殖和/或化学预防作用，在转基因腺癌小鼠前列腺（TRAMP）小鼠体内介导的时钟基因调节，这模拟了人类疾病的特征。我们相信，该提议的成功完成将建立i）褪黑激素（广泛使用的CAM方法）对抗PCa的潜力，和ii）褪黑激素的生物学效应的新分子机制。这可能有助于设计新的策略来管理PCa。