Chemoprevention by Black Raspberry of Oral Cancer Induced by Tobacco Carcinogens: Translational Studies

黑树莓对烟草致癌物诱发的口腔癌的化学预防：转化研究

• 批准号: 10558738
• 负责人: KARAM E EL-BAYOUMY
• 金额: $ 29.71万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558738
• 关键词: Allelic Imbalance; Anthocyanins; Antioxidants; Aromatic Polycyclic Hydrocarbons; Base Excision Repairs; Benzo(a)pyrene; Biological Assay; Black race; Carcinogens; Cells; Chemoprevention; Chemopreventive Agent; Clinical Trials; Cohort Studies; Cytoprotection; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Inhibition; DNA Structure; DNA lesion; Data; Deoxyribonucleotides; Development; Dietary Intervention; Disease; Drug Metabolic Detoxication; Eating; Enteral; Environment; Environmental Carcinogens; Environmental Exposure; Enzymes; Epithelium; Epoxy Compounds; Etiology; Event; Excision; Exposure to; Freeze Drying; Future; Gel; Gene Mutation; Glutathione Disulfide; Glycols; Head and Neck Cancer; Heterogeneity; Human; In Vitro; Intervention; Knock-out; Literature; Loss of Heterozygosity; Malignant Epithelial Cell; Minerals; Molecular; Mus; Mutagenesis; Mutation; N' -nitrosonornicotine; NADP; Nitrosamines; Nucleotide Excision Repair; OGG1 gene; Oral; Oral Leukoplakia; Oral cavity; Oral mucous membrane structure; Oxidation-Reduction; Participant; Patients; Phase; Physical condensation; Powder dose form; Prevention; Prevention approach; Prevention strategy; Prevention trial; Pyrenes; Raspberries; Reaction; Recycling; Reduced Glutathione; Ribonucleotides; Risk Factors; Role; Scheme; Smoker; Structure; Surface; TP53 gene; Time; Tissues; Tobacco; Tobacco smoke; Tobacco smoking behavior; Tobacco use; Tobacco-Associated Carcinogen; Tobacco-Related Carcinoma; Topical application; Transfection; Tumor Suppressor Genes; Voice; Xenobiotic Metabolism; adduct; carcinogenesis; cofactor; design; disorder control; drinking; environmental tobacco smoke; foodborne; former smoker; genomic locus; high risk; insight; keratinocyte; malignant mouth neoplasm; mouse model; mouth squamous cell carcinoma; multimodality; neoplastic; novel; oxidative DNA damage; oxidative damage; preservation; prevent; public health relevance; repair enzyme; repair function; repaired; smoking cessation; targeted treatment; translational study

Project Abstract Tobacco use remains a high risk factor for oral squamous cell carcinoma (OSCC) resulting from exposure to potent tobacco carcinogens including polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[a,l]pyrene (DB[a,l]P), benzo[a]pyrene (B[a]P) and tobacco-specific nitrosamines (TSNA) such as N’-nitrosonornicotine (NNN). To assess effects of these carcinogens on oral mucosa, we developed a novel OSCC mouse model using DB[a,l]P and its fjord region diol epoxide (DB[a,l]PDE). Importantly, we showed that dietary intervention with freeze-dried black raspberries (BRB) powder inhibited carcinogen-induced DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity. We have also established that BRB reduce formation and/or enhance repair of bulky adducts in vitro, but, the mechanisms by which BRB reduce DNA damage remain to be fully elucidated. Considering the varied structures of DNA adducts, we will focus on BRB effects on the nucleotide excision repair (NER) and base-excision repair (BER) enzymes. Based on the abundant phenolic compounds in BRB e.g. anthocyanins, it is logical to propose that BRB help preserve the cellular redox poise, enhance redox scavenging and thus function to prevent oxidative DNA damage; our data support this proposition. In addition to their cytoprotective functions, a specific cellular reducing equivalent-NADPH-functions in reductive biosynthetic reactions including conversion of ribonucleotides to deoxyribonucleotides (dNTPs) that are essential components for DNA repair. Based on these data, we hypothesize that BRB reduce DNA damage (cf. Scheme 1, Significance) in a multimodal fashion: 1) BRB enhance NER and BER function via preservation of key substrates and cofactors i.e. dNTPs and Mg2+, while maintaining an optimal, non-oxidized environment conducive to DNA repair; 2) BRB preserve the cellular redox status via efficient scavenging of reactive species that can inhibit DNA repair enzymes thereby reducing oxidative DNA damage. The proposed mechanistic studies entail two complementary, yet independent, Specific Aims: Aim 1A will investigate the effects of BRB on repair (NER, BER) of covalent tobacco carcinogen-DNA adducts and 8-OXO-dG in primary human oral keratinocyte cells that have been transfected with these adducts using our established assay. Aim 1B will determine the capacity of BRB to prevent oxidative damage in wild-type (OGG1+/+, a component of BER enzymes) and knockout (OGG1-/-) MEF cells. Concurrent studies, applicable to both subaims, will assess BRB effect on preservation of dNTP pools and key cellular redox poise parameters in a continuum of validated cells ranging from primary human oral keratinocytes, oral leukoplakia and OSCC cells. Aim 2 will determine for the first time the effects of local BRB delivery on formation of covalent DNA adducts and 8-OXO-dG in buccal cells of healthy smokers. The results could serve as the framework for future chemopreventive trials for addicted smokers who are unable to quit as well as non- or former-smokers who are exposed to environmental carcinogens.

项目摘要