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；

基本信息

批准号：
8848906
负责人：
Rita Ghosh
金额：
$ 8.16万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848906
关键词：
8-Oxo-2&apos -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 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 cell prostate cancer prevention prostate carcinogenesis research study response restoration tumor tumor growth tumor progression

项目摘要

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.

描述（由申请人提供）：具有临床意义的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表明，氧化应激信号传导可能是预防临床前列腺癌的合理目标。尽管 SELECT 试验的失败反对这种方法；我们建议，能够中和几类活性物质的抗氧化剂混合物将是一种极好的预防措施。我们认为，几类活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。我们初步发表的结果表明，与未接受激素治疗的动物相比，经激素刺激后发生前列腺上皮内瘤变 (PIN) 的大鼠体内的 NADPH：醌氧化还原酶 (NQO1)（一种前列腺中的 II 相解毒酶）水平是检测不到的。为了与我们的抗氧化预防方法保持一致，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中的 NQO1 与未刺激的基础水平相当。此外，这种抗氧化剂组合的干预导致 PIN 患病率显着下降 (p = 0.04)。基于这些数据，我们建议检验以下假设：通过抗氧化剂组合恢复 NQO1 足以抑制炎症信号介导的 PIN 的发展和前列腺癌的进展。提出了三个具体目标。目标 1 将确定抗氧化剂在培养的永生化人前列腺上皮细胞、良性前列腺增生细胞以及来自 Nkx3.1 的前列腺上皮细胞中淬灭激素诱导的活性物质并恢复氧化还原平衡的能力； Pten复合突变小鼠。在目标 2 中，我们将使用多种人和小鼠前列腺上皮细胞和肿瘤细胞评估 NQO1 在前列腺癌发生过程中激素诱导的氧化应激中的作用。在目标 3 中，我们将确定通过上调 NQO1 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。将使用各种生物化学、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。这具有立即临床转化的潜力。此外，这些研究还可能导致其他靶点的开发，例如 NQO1 和/或它的前列腺癌管理调节因子。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.

DOI：
10.3390/ijms22041852
发表时间：
2021-02-12
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Batth IS;Huang SB;Villarreal M;Gong J;Chakravarthy D;Keppler B;Jayamohan S;Osmulski P;Xie J;Rivas P;Bedolla R;Liss MA;Yeh IT;Reddick R;Miyamoto H;Ghosh R;Kumar AP
通讯作者：
Kumar AP

DNA Methylation and Flavonoids in Genitourinary Cancers.