Phospho-sulindac for Lung Cancer Treatment

摘要 肺癌是癌症死亡的主要原因，5年生存率<15%。这一令人震惊 预后表明迫切需要新的有效治疗药物。磷酸-舒林酸（PS），a 我们开发的一种新化合物，抑制肺癌异种移植物的生长达87- 103%，消除了， 一项研究显示，3/7的肺癌肿瘤。除了显著的疗效外，PS还具有出色的安全性。 因此，PS具有成为治疗肺癌的有效药物的强大潜力。我们 初步资料表明，PS的抗癌作用的机制实质上是： 诱导氧化应激，从而激活氧化还原敏感的信号级联，进而阻断细胞周期 其作用是抑制肿瘤的生长、增殖和诱导细胞凋亡;最终结果是抑制肿瘤生长。的 PS引起的氧化应激的发展是由于：a）NADPH氧化酶的活化，其产生游离的 自由基超氧阴离子;和B）抑制细胞抗氧化系统的几个成员， 酶（硫氧还蛋白系统，过氧化物酶，细胞珠蛋白，超氧化物歧化酶）和化学 这些作用迅速增加了细胞内活性氧（ROS）的水平，从而使细胞内的谷胱甘肽（GSH）转移。 氧化还原平衡对氧化应激。在体内，抗氧化剂N-乙酰半胱氨酸和PS的联合给药 抑制氧化应激并消除PS对肺癌异种移植物的抗癌作用。我们 假设PS是一种高效安全的治疗肺癌的药物， 主要是通过诱导氧化应激。为了评估这一假设，我们提出了以下具体的 目的：1）在动物肿瘤模型中评估PS对肺癌的疗效： 研究包括反映肺癌遗传亚型的其他细胞系的异种移植物， 肺癌的转基因模型。2)在患者来源的肺癌异种移植物中获得了显著疗效。他们 提供了很好的预测药物在人类中的疗效;我们将研究具有KRAS或EGFR突变的肿瘤。 （3）对PS诱导氧化应激的分子靶点进行体内外研究， 介导其抗癌作用的下游信号通路。我们将评估主要贡献者， 氧化应激和氧化应激下游的信号传导途径。

ABSTRACT Lung cancer is the leading cause of cancer deaths, with a 5-year survival rate of <15%. This alarming prognosis makes clear the urgent need for new efficacious agents for its treatment. Phospho-sulindac (PS), a novel compound developed by us, inhibits the growth of lung cancer xenografts by 87-103%, eliminating, in one study, 3/7 lung cancer tumors. In addition to its remarkable efficacy, PS has an exceptional safety profile. Thus PS has a strong potential of becoming an efficacious agent for the treatment of lung cancer. Our preliminary data indicate that the mechanism of the anti-cancer effect of PS is, in its essence, the following: PS induces oxidative stress, which activates redox-sensitive signaling cascades, which in turn block cell cycle progression, inhibit proliferation and induce apoptosis; the end result is inhibition of tumor growth. The development of oxidative stress by PS is due to: a) activation of NADPH oxidase, which generates the free radical superoxide anion; and b) suppression of several members of the antioxidant system of the cell, both enzymatic (the thioredoxin system, peroxiredoxin, cytoglobin, superoxide dismutase) and chemical (glutathione).These effects increase rapidly the cellular levels of reactive oxygen species (ROS) shifting the redox balance towards oxidative stress. In vivo, co-administration of the antioxidant N-acetyl-cysteine and PS suppresses oxidative stress and eliminates the anticancer effect of PS on lung cancer xenografts. Our hypothesis is that PS is a highly effective and safe agent for the treatment of lung cancer acting predominantly by inducing oxidative stress. To evaluate this hypothesis, we propose the following specific aims: 1) Assess the efficacy of PS against lung cancer in animal tumor models: We will expand the efficacy studies to include xenografts of additional cell lines mirroring the genetic subtypes of lung cancer and a transgenic model of lung cancer. 2) Validate efficacy results in patient-derived lung cancer xenografts. They provide excellent prediction of drug efficacy in humans; we will study tumors with KRAS or EGFR mutations. And 3) Study in vitro and in vivo the molecular targets involved in the induction of oxidative stress by PS and the downstream signaling pathways that mediate its anticancer effect. We will evaluate the main contributors to oxidative stress and signaling pathways downstream of oxidative stress.