Phospho-sulindac for Lung Cancer Treatment

磷酸舒林酸用于肺癌治疗

• 批准号: 9754402
• 负责人: Basil Rigas
• 金额: $ 6.72万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754402
• 关键词: Address; Animal Model; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Biological Markers; Butane; Cancer Etiology; Cell Cycle Progression; Cell Line; Cells; Cessation of life; Chemicals; Clinical; Cysteine; Data; Development; Diagnosis; Disease; Dose; Drug Combinations; Early Diagnosis; Early treatment; Epidermal Growth Factor Receptor; Equilibrium; F2-Isoprostanes; Free Radicals; Genetic; Glutathione; Growth; Human; In Vitro; Incidence; Intravenous; KRAS2 gene; Lead; Link; Lung Neoplasms; MAP Kinase Gene; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Maximum Tolerated Dose; Mediating; Modeling; Molecular Target; Mus; Mutation; NADPH Oxidase; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Non-Steroidal Anti-Inflammatory Agents; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; PTEN gene; Patients; Pre-Clinical Model; Reactive Oxygen Species; Safety; Signal Pathway; Signal Transduction; Sulindac; Superoxide Dismutase; Superoxides; Survival Rate; System; TXN gene; Therapeutic Agents; Therapeutic Effect; Therapeutic Index; Transgenic Model; Work; Xenograft procedure; anti-cancer; base; cancer cell; cancer therapy; design; dityrosine; drug efficacy; efficacy study; in vivo; lung cancer prevention; lung small cell carcinoma; member; nanocarrier; novel; outcome forecast; peroxiredoxin; response; side effect; subcutaneous; tumor; tumor growth

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.

摘要 肺癌是癌症死亡的主要原因，5年生存率为15%。这令人担忧 预后表明迫切需要新的有效药物来治疗它。硫代磷酸(PS)，a 我们开发的新化合物，抑制肺癌移植瘤的生长87-103%，消除，在 一项研究显示，七分之三的肺癌肿瘤。除了显著的疗效外，PS还具有特殊的安全性。 因此，PS有很强的潜力成为治疗肺癌的有效药物。我们的 初步数据表明，PS的抗癌作用机理本质上是： 诱导氧化应激，激活氧化还原敏感的信号级联反应，进而阻断细胞周期 进展，抑制增殖和诱导凋亡；最终结果是抑制肿瘤生长。这个 PS的氧化应激是由于：a)NADPH氧化酶的激活，它产生了游离的 自由基超氧阴离子；以及b)抑制细胞抗氧化系统的几个成员，两者 酶(硫氧还蛋白系统、过氧化还蛋白、细胞球蛋白、超氧化物歧化酶)和化学 (谷胱甘肽)。这些效应迅速增加了细胞内活性氧物种(ROS)的水平，使 氧化还原平衡朝向氧化应激。体内抗氧化剂N-乙酰半胱氨酸和PS的联合应用 抑制氧化应激，消除PS对肺癌移植瘤的抗癌作用。我们的 假说PS是一种治疗肺癌的高效、安全的药物 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建议 目的：1)在动物肿瘤模型上评价PS对肺癌的疗效：我们将扩大其疗效 研究包括反映肺癌基因亚型的额外细胞系的异种移植和 肺癌转基因模型的建立。2)验证患者来源的肺癌异种移植的疗效。他们 为人类的药物疗效提供极好的预测；我们将研究具有KRAS或EGFR突变的肿瘤。 3)体内外研究PS诱导氧化应激的分子靶点。 介导其抗癌作用的下游信号通路。我们将对主要贡献者进行评估 氧化应激和氧化应激下游的信号通路。