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: 8624661
• 负责人: Chinthalapally V. Rao
• 金额: $ 28.05万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624661
• 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 Intervention; 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.

抽象的 该提案的总体目标是制定有效的化学预防策略和 了解他汀类药物组合抑制结肠肿瘤的分子机制 (3- 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 对抗结肠癌。结直肠癌是男性和女性中最常见的恶性肿瘤之一 美国的女性。在制定转化策略时，更好的方法是针对多个目标 信号通路选择性地促进肿瘤生长，从而提供 协同/累加功效。结肠肿瘤细胞通过内源性产生高水平的多胺 鸟氨酸脱羧酶（ODC）的激活。 DFMO 选择性抑制 ODC 活性，从而 内源性多胺合成和结肠肿瘤生长。对多胺运输的新见解 在肿瘤细胞中，caveolin-1 (cav-1) 和 SLC3A2 介导的途径表明新的方法 肿瘤细胞中有效的多胺调节所必需的。尽管 DFMO 抑制 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) 以及 AKT 和 Rho 信号传导的激活，导致肿瘤细胞增殖和侵袭增强。 我们的初步结果表明，瑞舒伐他汀与低剂量 DFMO 的组合可抑制 氧化偶氮甲烷 (AOM) 诱导的结肠异常隐窝病灶 (ACF) 和异常隐窝细胞增殖。我们的 体外和体内结果表明 cav-1 在结肠癌中发挥重要作用，他汀类药物表现出 部分通过调节 cav-1 抑制结肠肿瘤。因此，我们希望开发他汀类药物的组合 和 DFMO 用于结肠癌预防/治疗，了解 cav-1 在结肠癌中的作用及其 可能受到 miRNA 的调节。具体目标是 1) 确定瑞舒伐他汀的体内功效 （Crestor）在 F344 大鼠结肠癌发生模型中（最大耐受/最佳剂量选择；剂量- 反应效果；以及晋升/进展阶段的有效性（早期/晚期干预）。 2) 确定阿托伐他汀/瑞舒伐他汀和 DFMO 对病情进展的联合疗效 结肠 ACF（起始后/早期）或腺瘤（进展/晚期）至结肠腺癌 大鼠体内的形成。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的 miRNA 修饰并将这些结果与结肠肿瘤相关联 抑制。 3) 使用cav-1-/-敲除小鼠模型定义cav-1在结肠癌发生中的作用和 确定有或没有 DFMO 的他汀类药物对致癌物诱导的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 miRNA 对 结肠癌细胞中 cav-1 的调节，并评估他汀类药物和 DFMO 对结肠癌细胞的可能调节作用 cav-1 miRNA 调控。

项目成果

Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling.

eflornithine（DFMO）通过调节鸟氨酸脱羧酶信号传导来防止胰腺癌的进展。

• DOI: 10.1158/1940-6207.capr-14-0176
• 发表时间: 2014-12
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Mohammed A;Janakiram NB;Madka V;Ritchie RL;Brewer M;Biddick L;Patlolla JM;Sadeghi M;Lightfoot S;Steele VE;Rao CV
• 通讯作者: Rao CV

Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer.

通过瑞士瓦伐他汀和差甲基氨基氨酸的结合来增强NK细胞活性，从而有效地对结肠癌的化学预防疗效。

• DOI: 10.1038/srep37046
• 发表时间: 2016-11-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Janakiram NB;Mohammed A;Bryant T;Zhang Y;Brewer M;Duff A;Biddick L;Singh A;Lightfoot S;Steele VE;Rao CV
• 通讯作者: Rao CV

Improved innate immune responses by Frondanol A5, a sea cucumber extract, prevent intestinal tumorigenesis.

• DOI: 10.1158/1940-6207.capr-14-0380
• 发表时间: 2015-04
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Janakiram NB;Mohammed A;Bryant T;Lightfoot S;Collin PD;Steele VE;Rao CV
• 通讯作者: Rao CV

Anti-inflammatory phytochemicals for chemoprevention of colon cancer.

• DOI: 10.2174/15680096113139990036
• 发表时间: 2013-05
• 期刊: Current cancer drug targets
• 影响因子: 3
• 作者: Venkateshwar Madka;C. Rao

Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice.

• DOI: 10.1002/ijc.27456
• 发表时间: 2012-10-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Mohammed, Altaf;Qian, Li;Janakiram, Naveena B.;Lightfoot, Stan;Steele, Vernon E.;Rao, Chinthalapally V.
• 通讯作者: Rao, Chinthalapally V.