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

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。前列腺癌患者中存在氧化应激标志物，表明氧化应激信号可能是预防临床前列腺癌的合理靶点。虽然失败的选择试验反对这种方法，我们建议，鸡尾酒的抗氧化剂的能力，以中和几类活性物质将是一个很好的预防措施。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，NADPH：醌氧化还原酶（NQO 1），一种II期解毒酶在前列腺激素刺激大鼠前列腺上皮内瘤（PIN）的水平是检测不到的激素相比，幼稚的动物。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（专利申请中）。有趣的是，接受抗氧化剂的大鼠的NQO 1与未受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患病率显著降低（p = 0.04）。基于这些数据，我们提出了一个假设，即通过抗氧化剂的组合恢复NQO 1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; Pten化合物突变小鼠的前列腺上皮细胞中淬灭前列腺素诱导的反应性物质并恢复氧化还原平衡的能力。在目标2中，我们将使用多种人类和小鼠前列腺上皮细胞和肿瘤细胞来评估NQO 1在前列腺癌发生过程中前列腺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NQO 1来维持氧化还原平衡是否足以预防Nkx3.1; Pten化合物突变小鼠模型中的前列腺癌。将使用各种生物化学、分子生物学和基因组学方法。这里提出的实验将建立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。进一步的这些研究也可能导致开发其他靶点，如NQO 1和/或其调节剂用于前列腺癌管理。

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.