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

描述（由申请人提供）：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。非甾体抗炎药（NSAIDs）已被证明可以显著降低结直肠癌的发病率和死亡风险，但环氧化酶（COX）抑制和生理上重要的前列腺素抑制所产生的不良副作用限制了它们在化学预防中的长期使用。据报道，非甾体抗炎药舒林酸对家族性腺瘤性息肉病患者的癌前腺瘤治疗非常有效，并且在临床前动物模型中显示出有希望的抗癌活性。我们的初步数据显示，sulindac （SS）的硫化物代谢物可以有效抑制人类结肠肿瘤细胞的侵袭，这表明该药物可能抑制与转移相关的生物学过程。其机制似乎涉及抑制转录因子NF-kB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震动（QKI）。我们的研究结果表明，这种机制可能不需要COX抑制，因为非COX抑制衍生物sulindac sulfide amide （SSA）可以明显诱导QKI并抑制结肠肿瘤细胞的侵袭。SSA明显比SS更有效，因为它具有良好的口服生物利用度，并且具有独特的组织分布模式，可以在肺和肝脏两个主要转移部位达到高浓度

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.