Chemoprevention by black raspberry in oral cancer induced by DB[a,l]P in mice

黑树莓对 DB[a,l]P 诱导的小鼠口腔癌的化学预防作用

• 批准号: 9252235
• 负责人: KARAM E EL-BAYOUMY
• 金额: $ 27.93万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252235
• 关键词: Acids; Affect; Animal Model; Animals; Anthocyanins; Antioxidants; Apoptosis; Biochemical; Biopsy; Carcinogens; Carcinoma; Carcinoma in Situ; Cell Culture Techniques; Cell Cycle Regulation; Cell Proliferation; Cells; Cessation of life; Cheek structure; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Clinical Chemoprevention; Clinical Research; Cultured Cells; Cyclin D1; DNA Adduction; DNA Adducts; DNA Damage; DNA lesion; Development; Diagnostic Procedure; Diet; Disease; Disease Progression; Drug Metabolic Detoxication; Dysplasia; Environment; Epoxy Compounds; Etiology; Event; Exhibits; Flavonols; Freeze Drying; Frequencies; Future; Genes; Glycols; Hamsters; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histopathology; Human; Hyperplasia; In Vitro; Incidence; Induction of Apoptosis; Lead; Lesion; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Target; Mus; Mutation; Neck Cancer; Operative Surgical Procedures; Oral; Oral Diagnosis; Oral Leukoplakia; Oral cavity; Organ; Outcome; PTGS2 gene; Pathway interactions; Powder dose form; Prevention; Prevention strategy; Proteins; Pyrenes; Raspberries; Recurrence; Retinoblastoma Protein; Rodent; Site; Smoker; Squamous cell carcinoma; TP53 gene; Techniques; Testing; Tobacco smoking; Tobacco-Associated Carcinogen; Tongue; Translating; Validation; cancer cell; cancer type; carcinogenesis; chemical carcinogen; cigarette smoking; design; dimethylbenzanthracene; exposed human population; ferulic acid; high risk; improved; inhibitor/antagonist; innovation; insight; kaempferol; malignant mouth neoplasm; molecular marker; mouth squamous cell carcinoma; oral tissue; oral tumorigenesis; phenolic acid; prevent; public health relevance; tumor; tumor progression

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck region; in the USA, over 45,000 cases and about 11,000 deaths from the disease occur annually. Progress in the prevention and control of OSCC has been hampered by the lack of appropriate animal models that would reflect human exposure. Tobacco smoking is considered a major etiological factor in the development of oral cancer. An attractive animal model would be one where tumors resulting from chronic exposure of the animal to chemical carcinogens present in cigarette smoke, would recapitulate the biochemical, molecular and cellular alterations observed in human OSCC during the development of the disease. We have developed such a model and propose to apply it to chemoprevention. Previous studies have demonstrated the ability of diets containing 5-10% freeze-dried black raspberry (BRB) powder to inhibit the development of chemically-induced cancers in multiple organ sites in rodents including the oral cavity. 7,12-Dimethylbenz(a)anthracene (DMBA) induced squamous cell carcinomas (SCC) in the hamster cheek pouch. However, DMBA is not present in the environment and the hamster cheek pouch model may not be applicable to humans. We have shown that the tobacco carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) can induce SCC in oral tissues. Its metabolite, (¿)-anti- DB[a,l]PDE is a potent and specific carcinogen in oral tissues in mice and the mutational profiles induced by DB[a,l]P and its diol epoxide are very similar, consistent with the formation of stable covalent DNA adducts (Preliminary Results). Mutations in both lacI and p53 genes in oral tissues of mice treated with DB[a,l]P are similar to those observed in OSCC in humans. In addition, DNA lesions induced by DB[a,l]P and (¿)-anti- DB[a,l]PDE in the oral tissues of mice were detected by LC-MS/MS. Preliminary Results showed 5% BRB powder or 0.025% kaempferol (KF) in diets significantly inhibited DB[a,l]P-DNA adduct formation in the oral cavity of mice treated with DB[a,l]P. We hypothesize that BRB and its active components including BRB powder and its anthocyanins enriched extract, protocatechuic acid (a major metabolite of anthocyanins), KF, and ferulic acid (components of raspberries) will inhibit oral tumorigenesis and do so by multiple mechanisms including: inhibition of DNA damage and cell proliferation, modulation of genes critical to cancer progression, and induction of apoptosis (Aim 1), and will also exhibit the same mechanistic effects in human oral cell cultures representing different stages of the disease (Aim 2). Aim 2 will extend and translate our findings to future clinical studies. Innovation: This application is he first to examine the chemopreventive effects of BRB and related agents on the induction of OSCC in a highly relevant animal model. The mechanisms of chemoprevention by BRB will also be investigated. Relevance/Impact: The results of this study using a relevant animal model for OSCC will provide mechanistic insights that are urgently needed to formulate the most effective strategies for future clinical chemoprevention trials by BRB and its active compounds.

描述（由适用提供）：口腔鳞状细胞癌（OSCC）是头部和颈部最常见的癌症；在美国，每年有超过45,000例病例和大约11,000例死亡。缺乏反映人类暴露的适当动物模型，阻碍了OSCC预防和控制的进展。吸烟被认为是口腔癌发展的主要病因。一种有吸引力的动物模型将是一种因动物在香烟烟雾中的慢性暴露于化学致癌物而导致的肿瘤，将概括人类OSCC在疾病发展过程中观察到的生化，分子和细胞改变。我们已经开发了这样的模型和建议，将其应用于化学预防。先前的研究表明，含有5-10％冻干黑色覆盆子（BRB）粉末的饮食能够抑制包括口腔腔内在内的多个器官中化学诱导的癌症的发展。 7,12-二甲基苯子（A）蒽（DMBA）在仓鼠脸颊袋中诱导鳞状细胞癌（SCC）。但是，DMBA不存在于环境中，仓鼠脸颊袋模型可能不适用于人类。我们已经表明，烟草致癌物Dibenzo [a，l] pyrene（db [a，l] p）可以在口腔组织中诱导SCC。代谢产物，（�） - 抗DB [A，L] PDE是小鼠口腔组织中的潜在和特异性致癌物，并且由db [a，l] p及其二醇环氧化物诱导的突变特征非常相似，与稳定的协调DNA的形成一致（PRELIMIMINALIMY FALIDS）。用DB [A，L] P处理的小鼠口腔组织中LACI和p53基因的突变与人类OSCC中观察到的突变相似。另外，通过LC-MS/MS检测到由小鼠口腔组织中的DB [A，L] P和（A，L] PDE诱导的DNA病变。初步结果显示饮食中的5％BRB粉末或0.025％Kaempferol（KF）显着抑制了用DB [A，L] p处理的小鼠口腔中的DB [A，L] P-DNA添加剂形成。我们假设BRB及其活性成分在内，包括BRB粉及其花青素富集提取物，方案chucci酸（一种主要的花青素代谢产物），KF和系蛋白酸和系蛋白酸（覆盆子的成分）（成分）（覆盆子的成分）将抑制口腔肿瘤的损害和造成多个癌症的癌症典范的癌症，DNA的癌症繁殖率包括在内：诱导凋亡（AIM 1），并且还将在代表该疾病不同阶段的人口腔细胞培养物中表现出相同的机械作用（AIM 2）。 AIM 2将扩展并将我们的发现转化为未来的临床研究。创新：该应用是他首先检查BRB和相关药物对高度相关动物模型中OSCC诱导的化学预防作用。也将研究BRB化学预防的机制。相关性/影响：本研究的结果使用相关动物模型进行OSCC提供机械见解，这些见解迫切需要，以制定BRB及其活性化合物的未来临床化学预防试验的最有效策略。