A synthetic triterpenoid in breast cancer chemoprevention

乳腺癌化学预防中的合成三萜类化合物

• 批准号: 7752768
• 负责人: Anupam Bishayee
• 金额: $ 7.7万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752768
• 关键词: Acids; Animal Model; Animals; Anthracenes; Apoptosis; Apoptosis Promoter; Apoptotic; Asians; Attenuated; Biochemical; Biological; Biological Assay; Breast Cancer Cell; Breast Cancer Prevention; Breast Carcinoma; Cancer cell line; Carcinogens; Caspase; Cause of Death; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; Country; Data; Development; Diet; Disease; Dose; Estrogen Receptors; Estrogens; Event; Experimental Neoplasms; Female; Gene Expression; Gene Family; Genes; Growth; Growth Factor; Growth and Development function; Human; In Vitro; Incidence; India; Induction of Apoptosis; Inhibition of Cell Proliferation; Knowledge; Lead; Location; MCF7 cell; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Maximum Tolerated Dose; Mediating; Medicinal Plants; Medicine; Modeling; Molecular; Molecular Genetics; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Plants; Play; Preventive; Proteins; Rattus; Regulatory Pathway; Relative (related person); Reporting; Research; Rest; Risk; Role; S-Phase Fraction; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sprague-Dawley Rats; Staging; Study Section; TP53 gene; Tamoxifen; Terpenes; Therapeutic; Time; Triterpenes; Triterpenoid Compound; Tumor Suppressor Genes; United States; Woman; amooranin; analog; anticancer research; base; cancer chemoprevention; clinically relevant; combat; cytochrome c; design; dietary supplements; dimethylbenzanthracene; feeding; human disease; in vivo; indexing; insight; killings; malignant breast neoplasm; novel; prevent; receptor expression; research study; soy; stem; tumor

DESCRIPTION (provided by applicant): Despite tremendous advances in medicine, breast cancer remains a leading cause of death in the United States as well as the rest of the world. It has been estimated that there will be 182,460 new cases and 40,480 deaths in the US in 2008 due to breast cancer in women. In view of the limited treatment options for patients with advanced stages of breast cancer, preventive control approaches, in particular chemoprevention could play an important role in therapeutic strategies to combat this disease. The plant-derived triterpenoids are used for medicinal purposes in many Asian countries, and some of these compounds are reported to have promising cancer-suppressive activity against various human breast cancer cells in vitro. Amooranin (AMR) is a triterpene acid isolated from the stem bark of Amoora rohituka, a well known medicinal plant native of India. AMR has been shown to inhibit the proliferation of human breast carcinoma cells in vitro as well as suppress rat mammary tumors in vivo. Recently, it has been shown that a novel synthetic analogue of amooranin (AMR-Me) has enhanced potency in the killing of human breast carcinoma cells in vitro because of its effects on genes associated with cell proliferation and apoptosis. This revised application is based on the hypothesis that AMR-Me would be clinically useful as a chemopreventive agent in human breast cancer. Accordingly, the objectives of this proposed research are to evaluate the chemopreventive effects of AMR-Me and to delineate its possible mechanism(s) of action in a well established, chemically-induced animal model of breast cancer, which closely mimics the human disease. Female Sprague-Dawley rats will be fed either a basal diet or diet supplemented with various levels of AMR-Me resulting in increasing doses of this terpenoid. The chemopreventive doses will be based on an experimentally-determined maximum tolerated dose (MTD). The AMR-Me treatment will start one week prior to a single oral (60 mg/kg) administration of 7,12-dimethylbenz(a)anthracene (DMBA), an established carcinogen for the initiation of mammary tumors. Animals will be palpated starting 4 weeks following DMBA administration to record the presence, location, and size of tumors. All animals will be sacrificed 18 weeks following the initiation of the mammary carcinogenesis with DMBA to conduct biological, biochemical, and molecular endpoint studies. The chemopreventive effect of AMR-Me will be assessed from the incidence, multiplicity, volume, and size distribution of mammary tumors. The influence of AMR-Me in modulating proliferation index, apoptotic index, and estrogen receptor expressions will be investigated. The possible mechanistic role of AMR-Me at the genetic and molecular pathways that lead to the induction of apoptosis and inhibition of cell proliferation will be thoroughly examined.

描述（由申请人提供）： 尽管医学方面取得了巨大进展，但乳腺癌仍然是美国以及世界其他地区的主要死亡原因。据估计，由于妇女的乳腺癌，在2008年，美国将有182,460例新病例和40,480例死亡。鉴于针对乳腺癌晚期患者的治疗选择有限，预防控制方法，特别是化学预防的方法可能在对抗这种疾病的治疗策略中起重要作用。在许多亚洲国家，植物来源的三萜用于药用，据报道，其中一些化合物在体外对各种人类乳腺癌细胞具有有希望的癌症抑制活性。 Amooranin（AMR）是一种从Amoora Rohituka的茎皮中分离出来的三萜酸，这是印度著名的药用植物。已显示AMR在体外抑制人类乳腺癌细胞的增殖，并抑制体内大鼠乳腺肿瘤。最近，已经显示出一种新型的amooranin（AMR-ME）的合成类似物在体外杀死人类乳腺癌细胞的效力增强了，因为它对与细胞增殖和凋亡相关的基因的影响。修订后的应用是基于以下假设：AMR-ME将在临床上作为人类乳腺癌的化学预防剂有用。因此，这项拟议的研究的目的是评估AMR-ME的化学预防作用，并在良好的，化学诱导的乳腺癌动物模型中描述其可能作用的可能机制，从而密切模仿人类疾病。雌性Sprague-Dawley大鼠将获得基础饮食或补充各种AMR-ME的饮食，从而增加了这种萜类化合物的剂量。化学预防剂量将基于实验确定的最大耐受剂量（MTD）。 AMR-ME治疗将在单个口服（60 mg/kg）给药7,12-二甲基苯苯（A）蒽（DMBA）之前开始，这是一种已建立的致癌物，用于哺乳动物肿瘤。 DMBA给药后4周，将对动物进行触诊，以记录肿瘤的存在，位置和大小。在使用DMBA进行乳腺癌发生后，将对所有动物进行18周的牺牲，以进行生物学，生化和分子终点研究。 AMR-ME的化学预防作用将根据乳腺肿瘤的发病率，多重性，体积和大小分布进行评估。将研究AMR-ME在调节增殖指数，凋亡指数和雌激素受体表达的影响。 AMR-ME在导致凋亡诱导和细胞增殖抑制的遗传和分子途径中的可能作用将得到彻底检查。