HMG-CoA Reductase and Polyamine Inhibitors for Prevention of Colorectal Cancer

HMG-CoA 还原酶和多胺抑制剂预防结直肠癌

• 批准号: 8244563
• 负责人: Chinthalapally V. Rao
• 金额: $ 28.91万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244563
• 关键词: AKT inhibition; Aberrant crypt foci; Accounting; Adenocarcinoma; Apoptosis; Azoxymethane; Carcinogens; Cardiovascular system; Cell Proliferation; Cells; Cessation of life; Chemopreventive Agent; Clinical; Clinical assessments; Colon Adenocarcinoma; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Crestor; Databases; Dose; Early treatment; Effectiveness; Exhibits; Generations; Goals; HCT116 Cells; Health Benefit; Human; Hydroxymethylglutaryl-CoA reductase; In Vitro; Inbred F344 Rats; Individual; Intervention; Knockout Mice; Malignant - descriptor; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Membrane; MicroRNAs; Modeling; Modification; Molecular; Mucous Membrane; Mus; Nitric Oxide; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Pathway interactions; Plasma; Play; Polyamines; Proto-Oncogene Proteins c-akt; Rattus; Regulation; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Testing; Tissues; Tumor Tissue; Woman; abstracting; adenoma; atorvastatin; base; cancer cell; cancer prevention; cancer therapy; caveolin 1; colon carcinogenesis; colorectal cancer prevention; crypt cell; extracellular; high risk; in vivo; inhibitor/antagonist; insight; male; men; mouse model; neoplastic cell; novel; novel strategies; preclinical evaluation; prevent; protective effect; response; rho; rosuvastatin; translational study; tumor; tumor growth; uptake

Abstract The overall goal of this proposal is to develop effective chemopreventive strategies and understand the molecular mechanism of colon tumor inhibition by a combination of statins (3- hydroxy-3methyl glutaryl CoA reductase (HMG-R) inhibitors) and polyamine inhibitor, DFMO against colon cancer. Colorectal cancer is one of the most common malignancies in both men and women in the US. In developing translational strategies, a preferable approach is to target multiple signaling pathways that selectively contribute towards tumor growth, so that it provides a synergistic/additive efficacy. Colon tumor cells produce high levels of polyamines endogenously through the activation of ornithine decarboxylase (ODC). DFMO selectively inhibits ODC activity and thereby endogenous polyamine synthesis and colon tumor growth. New insights into the transport of polyamines in tumor cells by caveolin-1 (cav-1) and SLC3A2 mediated pathways suggest that new approaches are needed for effective polyamine regulation in tumor cells. In spite of the fact that DFMO inhibits endogenous polyamine synthesis, tumor cells can still uptake extracellular polyamines through a cav-1 dependent endocytic mechanism. Further, Cav-1 plays an important role in the generation of nitric oxide (NO) and activation of AKT and Rho-signaling, leading to enhanced tumor cell proliferation and invasion. Our preliminary results suggest, that a combination of rosuvastatin with low-dose DFMO suppresses azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), and aberrant crypt cell proliferation. Our in vitro and in vivo results suggest that cav-1 plays an important role in colon cancer, and statins exhibit colon tumor inhibition in part by modulating cav-1. Therefore, we want to develop a combination of statin and DFMO for colon cancer prevention/treatment and understand the role of cav-1 in colon cancer and its possible regulation by miRNAs. Specific aims are 1) Determine the in vivo efficacy of Rosuvastatin (Crestor) in a F344 rat colon carcinogenesis model (maximum tolerated/optimal dose selection; dose- response effects; and effectiveness during promotion/progression stages (early/late interventions). 2) Determine the combinational efficacy of atorvastatin/rosuvastatin and DFMO on the progression of colonic ACF (post-initiation/early stage) or adenoma (progression/late stage) to colon adenocarcinoma formation in rats. We also want to determine the effect of statins and DFMO on the levels of cav-1, polyamines, ODC activity, NO (iNOS and eNOS activities), SLC3A2, AKT and Rho signaling proteins, miRNA modifications in colonic mucosa and tumor tissues and correlate these results with colon tumor inhibition. 3) Define the role of cav-1 in colon carcinogenesis using cav-1-/- knockout mouse model and determine the effect of statins with or without DFMO on carcinogen induced colon tumor formation in cav- 1-/- and cav-1+/+ mice. In addition, proposed research will elucidate the role of selective miRNAs on the regulation of cav-1 in colon cancer cells, and assess the possible modulatory role of statins and DFMO on cav-1 miRNA regulation.

摘要 这项提议的总体目标是制定有效的化学预防战略和 了解他汀类药物联合应用抑制结肠癌的分子机制 羟基-3甲基戊二酰辅酶A还原酶(HMG-R)抑制剂和多胺抑制剂DFMO 治疗结肠癌。结直肠癌是男性和女性最常见的恶性肿瘤之一。 美国的女性。在制定翻译策略时，更可取的方法是针对多个 选择性促进肿瘤生长的信号通路，因此它提供了一种 协同/相加功效。结肠肿瘤细胞通过内源性途径产生高水平的多胺 鸟氨酸脱羧酶(ODC)的激活。DFMO选择性地抑制ODC活性，从而 内源性多胺合成与结肠癌生长对多胺运输的新见解 在肿瘤细胞中通过小窝蛋白-1(Cav-1)和SLC3A2介导的途径表明，新的方法是 有效地调节肿瘤细胞中的多胺所需。尽管DFMO抑制了 内源性多胺合成，肿瘤细胞仍可通过Cav-1摄取细胞外多胺 依赖的内吞机制。此外，Cav-1在一氧化氮的生成中起着重要作用 (NO)和激活AKT和Rho信号，导致肿瘤细胞增殖和侵袭能力增强。 我们的初步结果表明，瑞舒伐他汀与小剂量DFMO联合使用可抑制 偶氮甲烷(AOM)诱导的结肠异常隐窝病灶(ACF)和异常的隐窝细胞增殖。我们的 体外和体内实验结果表明Cav-1在结肠癌中起重要作用，他汀类药物表现出 结肠癌抑制作用部分通过调节Cav-1来实现。因此，我们希望开发一种他汀类药物的组合 和DFMO在结肠癌防治中的作用及了解Cav-1在结肠癌及其相关基因中的作用 可能受到miRNAs的调控。具体目的是：1)测定瑞舒伐他汀的体内疗效 (Crestor)在F344大鼠结肠癌模型中(最大耐受/最佳剂量选择；剂量- 反应效果；以及晋升/进步阶段的有效性(早期/后期干预)。 2)确定阿托伐他汀/瑞舒伐他汀与DFMO联合用药的疗效。 结肠癌ACF(发病后/早期)或腺瘤(进展/晚期)至结肠腺癌 在大鼠体内形成。我们还想确定他汀类药物和DFMO对Cav-1水平的影响。 多胺、ODC活性、NO(iNOS和eNOS活性)、SLC3A2、AKT和Rho信号蛋白， 结肠粘膜和肿瘤组织中miRNA的修饰及其与结肠癌的相关性 抑制力。3)建立Cav-1基因敲除小鼠模型，研究Cav-1在结肠癌发生中的作用。 观察他汀类药物与DFMO合用对致癌物诱导的小鼠结肠肿瘤形成的影响。 1-/-和Cav-1+/+小鼠。此外，拟议的研究将阐明选择性miRNAs在 Cav-1在结肠癌细胞中的调控，并评价他汀类药物和DFMO对其可能的调节作用 Cav-1的miRNA调控。