MicroRNA, a new player for the NSAID sulindac to prevent colon cancer progression

MicroRNA，NSAID 舒林酸预防结肠癌进展的新成员

• 批准号: 8707735
• 负责人: Yaguang Xi
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707735
• 关键词: Accounting; Address; Adenomatous Polyposis Coli; Adverse effects; American Cancer Society; Amides; Angiogenesis Inhibition; Animal Model; Antineoplastic Agents; Aspirin; Bioinformatics; Biological Availability; Biological Markers; Biological Process; Cancer Patient; Cause of Death; Cell Adhesion; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Chemoprotection; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Drug or chemical Tissue Distribution; Epidemiologic Studies; FDA approved; Functional RNA; Future; Gene Targeting; General Population; Generic Drugs; Genes; Goals; Health; Human; In Vitro; Incidence; Individual; Induction of Apoptosis; Lead; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Meta-Analysis; MicroRNAs; Modeling; Molecular; Monitor; Mus; NF-kappa B; Names; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Oral; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Premalignant; Prevention; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publications; RNA Processing; Randomized; Reporting; Research; Risk; Role; Site; Sulfides; Sulindac; Sulindac Sulfide; Tissues; Toxic effect; Tumor Cell Invasion; Tumor Cell Line; Tumor Suppressor Proteins; United States; Xenograft Model; adenoma; advanced disease; anticancer activity; base; cancer cell; cancer initiation; cancer statistics; cellular imaging; drug development; effective therapy; high risk; imaging modality; improved; in vivo; insight; interest; metastasis prevention; metastatic colorectal; mouse model; neoplastic cell; novel; overexpression; pre-clinical; preclinical study; prevent; public health relevance; research study; response; treatment effect; tumor; tumor progression

DESCRIPTION (provided by applicant): According to the latest report of cancer statistics by American Cancer Society, colorectal cancer remains a leading cause of death from cancer in the United States. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to significantly reduce the incidence and risk of death from colorectal cancer, but adverse side effects resulting from cyclooxygenase (COX) inhibition and suppression of physiologically important prostaglandins limit their long-term use for chemoprevention. The NSAID, sulindac has been reported to be highly effective for the treatment of precancerous adenomas in individuals with familial adenomatous polyposis and has shown promising anticancer activity in preclinical animal models. Our preliminary data show that the sulfide metabolite of sulindac (SS) can potently inhibit the invasion of human colon tumor cells, which suggest that this drug may inhibit biological processes associated with metastasis. The mechanism appears to involve the inhibition of the transcription factor, NF-kB to suppress an oncogenic microRNA (miRNA) cluster, miR-17- 92, and induce a tumor suppressor protein, quaking (QKI) that plays an important role in regulating tumor cell adhesion and metastasis. Our results suggest that this mechanism might not require COX inhibition because a non-COX inhibitory derivative, sulindac sulfide amide (SSA) can apparently induce QKI and inhibit colon tumor cell invasion. SSA is appreciably more potent than SS as it has good oral bioavailability with a unique tissue distribution pattern to achieve high concentrations in lung and liver, two main sites of metastasis from colorectal cancer. We hypothesize that the mechanism by which sulindac inhibits tumor invasion is unrelated to its COX inhibitory activity; and the miR-17-92/QKI axis accounts or is partially responsible for this action. The proposed aims are to: 1) study the role of the miR-17-92/QKI axis in mediating anti-invasive activity of slindac in vitro; and 2) study the role of the miR-17-92/QKI axis in mediating anti-metastatic activity of sulindac in vivo. This application is being submitted in response to PA-12-214 and will address two research objectives: "determine the molecular pathways targeted by non-coding RNAs (ncRNAs) that predispose to cancer initiation or progression" and "determine whether interfering with oncogenic ncRNAs processing, target selection, or associated pathways prevent cancer progression". The proposed studies have the potential to impact human health by: 1) supporting the use of an FDA approved generic drug, sulindac, for the prevention of metastatic progression in patients with colorectal cancer; 2) evaluating a novel non-COX inhibitory of sulindac to accelerate its preclinical development; and 3) providing insight into ncRNA targets for the discovery of new biomarkers for clinical trials.

描述（申请人提供）：根据美国癌症协会最新的癌症统计报告，结直肠癌仍然是美国癌症死亡的主要原因。非甾体类抗炎药（NSAID）已被证明可显著降低结直肠癌的发病率和死亡风险，但环氧化酶（考克斯）抑制和生理上重要的三尖杉酯碱抑制导致的不良副作用限制了其用于化学预防的长期使用。据报道，NSAID舒林酸可高效治疗家族性腺瘤性息肉病患者的癌前腺瘤，并在临床前动物模型中显示出有前景的抗癌活性。我们的初步数据显示，舒林酸（SS）的硫化物代谢产物可以有效地抑制人结肠癌细胞的侵袭，这表明该药物可能抑制与转移相关的生物学过程。该机制似乎涉及抑制转录因子NF-κ B以抑制致癌microRNA（miRNA）簇miR-17- 92，并诱导在调节肿瘤细胞粘附和转移中起重要作用的肿瘤抑制蛋白quaking（QKI）。我们的研究结果表明，这种机制可能不需要考克斯抑制，因为非考克斯抑制衍生物，舒林酸硫酰胺（SSA）可以明显诱导QKI和抑制结肠肿瘤细胞的侵袭。SSA比SS更有效，因为它具有良好的口服生物利用度，具有独特的组织分布模式，可在肺和肝（两个主要转移部位）中达到高浓度 得了结肠直肠癌我们假设舒林酸抑制肿瘤侵袭的机制与其考克斯抑制活性无关; miR-17-92/QKI轴解释或部分负责该作用。拟议的目标是：1）研究miR-17-92/QKI轴在体外介导舒林酸的抗侵袭活性中的作用;和2）研究miR-17-92/QKI轴在体内介导舒林酸的抗转移活性中的作用。该申请是为了回应PA-12-214而提交的，将解决两个研究目标：“确定易导致癌症发生或进展的非编码RNA（ncRNA）靶向的分子途径”和“确定干扰致癌ncRNA加工，靶向选择或相关途径是否会阻止癌症进展”。拟议的研究有可能通过以下方式影响人类健康：1）支持使用FDA批准的仿制药舒林酸预防结直肠癌患者的转移进展; 2）评估舒林酸的新型非COX抑制剂，以加速其临床前开发; 3）为临床试验发现新的生物标志物提供对ncRNA靶点的深入了解。