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（由申请人提供）：口腔鳞状细胞癌（OSCC）是头颈部最常见的癌症；在美国，每年有超过 45,000 例病例和约 11,000 人死于该疾病。由于缺乏反映人类暴露情况的适当动物模型，口腔鳞癌的预防和控制进展受到阻碍。吸烟被认为是口腔癌发生的主要病因。一种有吸引力的动物模型是由于动物长期接触香烟烟雾中的化学致癌物而产生的肿瘤，该模型将重现在疾病发展过程中在人类 OSCC 中观察到的生化、分子和细胞变化。我们开发了这样一个模型，并建议将其应用于化学预防。先前的研究表明，含有 5-10% 冻干黑树莓 (BRB) 粉末的饮食能够抑制啮齿类动物多个器官部位（包括口腔）化学诱导的癌症的发展。 7,12-二甲基苯并(a)蒽 (DMBA) 诱导仓鼠颊囊中的鳞状细胞癌 (SCC)。然而，DMBA 不存在于环境中，仓鼠颊囊模型可能不适用于人类。我们已经证明烟草致癌物二苯并[a,l]芘 (DB[a,l]P) 可诱发口腔组织鳞状细胞癌。其代谢物 (¿)-抗 DB[a,l]PDE 在小鼠口腔组织中是一种强效且特异性的致癌物，DB[a,l]P 及其二醇环氧化物诱导的突变谱非常相似，与稳定共价 DNA 加合物的形成一致（初步结果）。用 DB[a,l]P 治疗的小鼠口腔组织中 lacI 和 p53 基因的突变与在人类 OSCC 中观察到的突变相似。此外，通过LC-MS/MS检测了小鼠口腔组织中DB[a,l]P和(¿)-抗DB[a,l]PDE诱导的DNA损伤。初步结果显示，饮食中添加 5% BRB 粉末或 0.025% 山奈酚 (KF) 可显着抑制 DB[a,l]P 治疗小鼠口腔中 DB[a,l]P-DNA 加合物的形成。我们假设 BRB 及其活性成分（包括 BRB 粉末及其富含花青素的提取物、原儿茶酸（花青素的主要代谢物）、KF 和阿魏酸（覆盆子的成分））将通过多种机制抑制口腔肿瘤发生，包括：抑制 DNA 损伤和细胞增殖、调节对癌症进展至关重要的基因、 和诱导细胞凋亡（目标 1），并且还将在代表疾病不同阶段的人类口腔细胞培养物中表现出相同的机制效应（目标 2）。目标 2 将我们的发现扩展并转化为未来的临床研究。创新：该应用首次在高度相关的动物模型中检查 BRB 和相关药物对诱导 OSCC 的化学预防作用。 BRB 的化学预防机制也将得到研究。相关性/影响：这项使用 OSCC 相关动物模型的研究结果将提供迫切需要的机制见解，以便为 BRB 及其活性化合物的未来临床化学预防试验制定最有效的策略。