THE PREVENTION OF B(A)P INDUCED CELL TRANSFORMATION BY ORGANOSULFUR COMPOUNDS

有机硫化合物预防 B(A)P 诱导的细胞转化

• 批准号: 7959140
• 负责人: Selina Faith Darling-Reed
• 金额: $ 11.73万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959140
• 关键词: Agar; Age; Benzo(a)pyrene; Breast; Cancer Etiology; Cancerous; Carcinogens; Cells; Cessation of life; Chemopreventive Agent; Colon; Comet Assay; Computer Retrieval of Information on Scientific Projects Database; DNA Adducts; DNA Damage; DNA Repair; DNA strand break; Development; Diet; Environment; Epidemiologic Studies; Epithelial Cells; Exposure to; Funding; Gene Expression; Grant; Human; Implant; Institution; Label; Liver; Lung; Malignant Neoplasms; Metabolic Biotransformation; Neoplastic Cell Transformation; Normal Cell; Nude Mice; Occupational; Pancreas; Pharmacologic Substance; Phenotype; Phosphorus 32; Prevention; Production; Research; Research Personnel; Resources; Source; Testing; Time; Treatment Protocols; United States; United States National Institutes of Health; Western Blotting; Woman; abstracting; allyl sulfide; cell transformation; cigarette smoking; diallyl disulfide; diallyl trisulfide; malignant breast neoplasm; prevent; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Abstract: Breast cancer is the leading cause of cancer related death in women between the ages of 40 and 55 and the second leading cause of cancer related death in women in the United States. Exposure to carcinogens in the environment, occupational setting, and diet are believed to be the reason for the discrepancy. Epidemiological studies demonstrate a positive association with breast cancer and cigarette smoke. Benzo(a)pyrene (B(a)P), a major component of cigarette smoke, has been shown to cause lung, liver, pancreatic, colon and breast cancer. B(a)P is biotransformed into reactive metabolites that produces DNA adducts and DNA strand breaks. Furthermore, B(a)P has been shown to transform human breast epithelial cells (MCF-10A)from a normal to a cancerous phenotype. Several OSCs Diallyl Sulfide (DAS), Diallyl Disulfide (DADS) and Diallyl Trisulfide (DATS) have been shown to prevent cancer by altering biotransformation. We hypothesize that these OSCs will prevent the transformation of normal human breast epithelial cells to a cancerous phenotype by altering the biotransformation of B(a)P thus preventing the production of B(a)P DNA adducts and the expression of genes involved in cell transformation. To test this hypothesis first we will treat MCF-10A cells with B(a)P and/or OSCs and determine if reactive metabolites are formed. Secondly, we will determine if B(a)P cause DNA strand breaks by comet assay analysis and DNA adducts via P32 Post labeling and if OSCs can prevent this DNA damage and enhance DNA repair over time. Next we will determine the ability of B(a)P to transform normal cell into a cancerous phenotype and the ability of OSCs to inhibit this transformation by treating the cells repeatedly with B(a)P and OSCs. The formation of colonies on soft agar will indicate the presence of transformed cells. Tumor development in nude mice implanted with these transformed cells will confirm neoplastic transformation. Finally, we will demonstrate that B(a)P and/or OSCs will alter the expression of genes associated with transformation and proliferation. Gene expression will be determined by Real Time PCR Array and confirmed by Western Blot Analysis. Results from this study will help elucidate the mechanism by which B(a)P causes breast cancer and how OSCs may prevent this cancer. Ultimately, better chemopreventive regimens and chemotherapeutic compounds would be developed for this research.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 抽象的： 乳腺癌是40至55岁女性癌症相关死亡的主要原因，也是美国女性癌症相关死亡的第二大主要原因。 据信在环境，职业环境和饮食中接触致癌物是差异的原因。流行病学研究表明，乳腺癌和香烟烟雾呈正相关。 苯并（a）pyrene（b（a）p）是香烟烟雾的主要组成部分，已被证明会导致肺，肝脏，胰腺，结肠癌和乳腺癌。 B（a）p生物转化为反应性代谢产物，产生DNA加合物和DNA链断裂。 此外，B（a）P已被证明可将人类乳腺上皮细胞（MCF-10A）从正常表型转化为癌变表型。 已经证明，几种OSCS dallyl硫化物（DAS），二烯醇二硫化物（DAD）和Dallyl Trisulfide（DATS）已证明可以通过改变生物转化来预防癌症。我们假设这些OSC将通过改变B（a）P的生物转化，从而防止正常人乳房上皮细胞转化为癌性表型，从而阻止B（a）P DNA加合物的产生以及与细胞转化有关的基因的表达。为了检验该假设，我们将用B（A）P和/或OSC对MCF-10A细胞进行处理，并确定是否形成了反应性代谢产物。 其次，我们将通过彗星测定分析和通过p32后标记来确定B（a）p是否会导致DNA链断裂，并且OSCS是否可以防止这种DNA损伤并随着时间的推移增强DNA修复。 接下来，我们将确定B（A）P将正常细胞转化为癌性表型的能力，以及OSC通过用B（a）P和OSC反复治疗细胞来抑制这种转化的能力。 软琼脂菌落的形成将表明存在转化的细胞。 用这些转化的细胞植入的裸鼠的肿瘤发育将证实肿瘤转化。 最后，我们将证明B（a）P和/或OSCS将改变与转化和增殖相关的基因的表达。 基因表达将由实时PCR阵列确定，并通过Western印迹分析确认。 这项研究的结果将有助于阐明B（a）P引起乳腺癌以及OSC如何预防该癌症的机制。最终，为这项研究开发了更好的化学预防方案和化学治疗化合物。