Oxidative stress in prostate cancer: Efficacy of antioxidants in Nkx3.1; Pten mod

前列腺癌中的氧化应激：Nkx3.1 中抗氧化剂的功效；

• 批准号: 8135056
• 负责人: Rita Ghosh
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135056
• 关键词: 8-Oxo-2' -Deoxyguanosine; Adenocarcinoma; Age; Age-Months; Androgens; Animal Model; Animals; Antioxidants; Benign Prostatic Hypertrophy; Biochemical; Biological; Cancer Patient; Cells; Chronic; Clinical; Complex; Culture Media; DNA; DNA Binding; DNA Markers; DNA strand break; Data; Development; Effectiveness; Elderly; Environment; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Estradiol; Euthanasia; Evaluation; Failure; Genomics; Glutathione Reductase; Hormones; Human; Immunohistochemistry; In Vitro; Incidence; Individual; Inflammation Mediators; Inflammatory; Interleukin-1; Intervention; Kinetics; Laboratories; Lead; Legal patent; Lesion; Lipids; Liver; Lung; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NQO1 gene; Neoplasm Metastasis; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Phase; Prevalence; Prevention approach; Process; Production; Prostate; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Proteins; Publishing; Quinones; Rattus; Reactive Oxygen Species; Regulation; Repression; Role; Selenium; Seminal Vesicles; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Solvents; Staging; Stress; Superoxide Dismutase; Supplementation; TNF gene; Testing; Testosterone; Time; Tissues; Toxic effect; Transactivation; Transcriptional Regulation; Translations; Tumor Burden; Up-Regulation; Vitamin E; Weight; Western Blotting; Wild Type Mouse; androgen independent prostate cancer; animal tissue; base; bone; cancer cell; cancer prevention; catalase; chemokine; clinically significant; cytokine; glutathione peroxidase; hormone metabolism; human disease; in vivo Model; intraepithelial; lymph nodes; macromolecule; mutant mouse model; neoplastic; neoplastic cell; novel; oxidative damage; p65; pre-clinical; prevent; prophylactic; prostate cancer prevention; prostate carcinogenesis; public health relevance; research study; response; restoration; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The long latency in clinically significant prostate cancer development provides numerous intervention opportunities. The existence of oxidative stress markers in prostate cancer patients suggests that oxidative stress signaling may be a reasonable target to prevent clinical prostate cancer. Although the failure of the SELECT trial argues against this approach; we propose that a cocktail of antioxidants with the capacity to neutralize several classes of reactive species would be an excellent prophylactic remedy. We argue that several classes of reactive species are produced from cellular metabolism therefore a single or a combination of two antioxidants (like the SELECT trial) is not only archaic but also absurd. Our preliminary published results show that level of NADPH: Quinone Oxidoreductase (NQO1), a phase II detoxifying enzyme in the prostate from hormone stimulated rats that develop Prostatic Intraepithelial Neoplasia (PIN) is undetectable compared to hormone naive animals. In keeping with our antioxidant prevention approach we developed a combination of antioxidants (patent pending). Interestingly, NQO1 in rats receiving antioxidants was comparable to that of the unstimulated basal level. Further, intervention with this combination of antioxidants caused significant decrease (p = 0.04) in prevalence of PIN. Based on these data we propose to test the hypothesis that restoration of NQO1 by a combination of antioxidants is sufficient to inhibit inflammatory signaling-mediated development of PIN and progression to prostate cancer. Three specific aims have been proposed. Aim 1 will determine the ability of the antioxidant(s) to quench hormone-induced reactive species and restore redox balance in cultured immortalized human prostate epithelial, benign prostate hyperplasia as well as prostate epithelial cells from the Nkx3.1; Pten compound mutant mice. In aim 2 we will evaluate the role of NQO1 in hormone-induced oxidative stress during prostate carcinogenesis using a variety of human and mouse prostate epithelial and tumor cells. In aim 3 we will determine whether maintaining redox balance through upregulation of NQO1 is sufficient to prevent prostate cancer in Nkx3.1; Pten compound mutant mouse model. A variety of biochemical, molecular biological and genomics approaches will be used. Experiments proposed here will establish the ability of a combination of antioxidants to prevent clinical prostate cancer. This has the potential for immediate clinical translation. Further these studies may also lead to the development of additional targets such as NQO1 and or its regulators for prostate cancer management. PUBLIC HEALTH RELEVANCE: Reactive species produced from cellular metabolism leads to changes in inflammatory signaling that can lead to neoplastic changes. Incapability to neutralize these reactive species and their downstream biological effects leads to oxidative stress, an environment that enables cancer progression. Our approach to break this chain is to use a cocktail of antioxidants that can quench several classes of reactive species. Our results show that such a cocktail inhibits the preliminary inflammatory changes associated with prostate cancer. In this proposal we will (i) understand the role of each of the components in quenching oxidative stress-induced inflammatory signaling in the prostate; (ii) establish the ability of the cocktail to prevent oxidative stress and therefore clinical prostate cancer using a preclinical animal model that most appropriately mimics the human disease; and (iii) identify novel targets for intervention through understanding the role of NQO1 in prostate carcinogenesis.

描述（由申请人提供）：临床显著前列腺癌发展的长潜伏期提供了许多干预机会。前列腺癌患者体内氧化应激标志物的存在提示氧化应激信号可能是临床预防前列腺癌的合理靶点。尽管SELECT试验的失败反对这种方法；我们建议，一种鸡尾酒的抗氧化剂的能力，中和几类活性物质将是一个极好的预防补救措施。我们认为，几种反应性物质是由细胞代谢产生的，因此单一或两种抗氧化剂的组合（如SELECT试验）不仅过时而且荒谬。我们初步发表的研究结果表明，与未使用激素的动物相比，激素刺激的前列腺上皮内瘤变（PIN）大鼠的前列腺内II期解毒酶NADPH：醌氧化还原酶（NQO1）的水平是不可检测的。为了与我们的抗氧化剂预防方法保持一致，我们开发了一种抗氧化剂组合（正在申请专利）。有趣的是，接受抗氧化剂的大鼠的NQO1与未受刺激的基础水平相当。此外，使用这种抗氧化剂组合进行干预可显著降低PIN患病率（p = 0.04）。基于这些数据，我们提出验证抗氧化剂组合恢复NQO1足以抑制炎症信号介导的PIN发展和前列腺癌进展的假设。提出了三个具体目标。目的1将确定抗氧化剂在培养的永生化人前列腺上皮、良性前列腺增生以及来自Nkx3.1的前列腺上皮细胞中抑制激素诱导的活性物质和恢复氧化还原平衡的能力；Pten复合突变小鼠。在目的2中，我们将利用多种人类和小鼠前列腺上皮细胞和肿瘤细胞来评估NQO1在前列腺癌变过程中激素诱导的氧化应激中的作用。在目的3中，我们将确定通过上调NQO1来维持氧化还原平衡是否足以预防Nkx3.1中的前列腺癌；Pten复合突变小鼠模型。将使用多种生化、分子生物学和基因组学方法。这里提出的实验将确定抗氧化剂组合预防临床前列腺癌的能力。这具有立即进行临床转化的潜力。进一步的这些研究也可能导致其他靶点的发展，如NQO1和或其调节因子用于前列腺癌的治疗。