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

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

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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（由申请人提供）：根据美国癌症学会的癌症统计数据的最新报告，大肠癌仍然是美国癌症死亡的主要原因。非甾体类抗炎药（NSAIDS）已被证明可显着降低结直肠癌死亡的发生率和死亡风险，但是环氧酶（COX）抑制和抑制生理上重要的Prostaglandins造成的不良副作用限制了其长期使用其对化学的使用。据报道，NSAID，Sulindac对于患有家族性腺瘤性息肉病的个体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，苏莱达克（SS）的硫化物代谢产物可以有效抑制人类结肠肿瘤细胞的侵袭，这表明该药物可以抑制与转移相关的生物学过程。该机制似乎涉及转录因子NF-KB的抑制，以抑制致癌性microRNA（miRNA）簇，miR-17-92，并诱导肿瘤抑制蛋白，质量（QKI），在调节肿瘤细胞粘附和转移中起着重要作用。我们的结果表明，这种机制可能不需要COX抑制作用，因为非抑制衍生物，苏氏硫化物酰胺（SSA）显然可以诱导QKI并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，可在肺和肝脏中获得高浓度从结直肠癌。我们假设Sulindac抑制肿瘤侵袭的机制与其Cox抑制活性无关。 MiR-17-92/QKI轴帐户或部分负责此操作。拟议的目的是：1）研究miR-17-92/qki轴在体外介导抗侵入活性中的作用； 2）研究miR-17-92/QKI轴在体内介导硫酸的抗转移活性中的作用。该应用是针对PA-12-214提交的，并将解决两个研究目标：“确定易于癌症开始或进展的非编码RNA（NCRNA）靶向的分子途径”，并确定干扰致癌NCRNAS处理，靶标的选择，相关途径，或相关的途径预防癌症的进展。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认可的仿制药Sulindac，以预防结直肠癌患者的转移性进展； 2）评估新型的非cox抑制硫酸抑制性，以加速其临床前的发育； 3）为发现新生物标志物的临床试验提供了洞察力。