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

基本信息

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
项目类别：
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

项目摘要

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) 已被证明可以显着降低结直肠癌的发病率和死亡风险，但环加氧酶 (COX) 抑制和生理上重要的前列腺素抑制导致的不良副作用限制了其长期用于化学预防。据报道，非甾体抗炎药舒林酸对于治疗家族性腺瘤性息肉病患者的癌前腺瘤非常有效，并且在临床前动物模型中显示出有希望的抗癌活性。我们的初步数据表明，舒林酸的硫化物代谢物（SS）可以有效抑制人结肠肿瘤细胞的侵袭，这表明该药物可能抑制与转移相关的生物过程。该机制似乎涉及抑制转录因子 NF-kB，以抑制致癌 microRNA (miRNA) 簇 miR-17-92，并诱导肿瘤抑制蛋白 quaking (QKI)，该蛋白在调节肿瘤中发挥重要作用细胞粘附和转移。我们的结果表明，这种机制可能不需要 COX 抑制，因为非 COX 抑制衍生物舒林酸硫酰胺 (SSA) 可以明显诱导 QKI 并抑制结肠肿瘤细胞侵袭。 SSA 明显比 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）中实现高浓度来自结直肠癌。我们推测舒林酸抑制肿瘤侵袭的机制与其COX抑制活性无关； miR-17-92/QKI 轴解释或部分负责这一作用。拟议的目的是：1）研究miR-17-92/QKI轴在介导斯林达体外抗侵袭活性中的作用； 2）研究miR-17-92/QKI轴在介导舒林酸体内抗转移活性中的作用。该申请是针对 PA-12-214 提交的，将解决两个研究目标：“确定非编码 RNA (ncRNA) 所针对的易导致癌症发生或进展的分子途径”和“确定是否干扰致癌 ncRNA”加工、靶标选择或相关途径可预防癌症进展”。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来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) 提供对 ncRNA 靶标的深入了解，以发现用于临床试验的新生物标志物。