Antioxidants and Antiinflammatory in Colorectal Cancer

结直肠癌中的抗氧化剂和抗炎药

• 批准号: 7743576
• 负责人: Ah-Ng Tony Kong
• 金额: $ 27.87万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-22 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743576
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Azoxymethane; Biological Markers; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogenesis Inhibition; Carcinogenesis Mechanism; Caspase; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Survival; Chemopreventive Agent; Cleaved cell; Clinical Trials; Colitis; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Curcumin; Cyclin D1; Cytoprotection; Data; Dietary Phytochemical; Dinoprostone; Dose; Enzyme Inhibition; Enzymes; Genes; Genetic; Glutathione Transferase mu; Goals; Growth; HT29 Cells; Human; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intestinal Cancer; Intestinal Neoplasms; Intestines; Isothiocyanates; Knowledge; Leukotriene B4; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Malignant Neoplasms; Measurement; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Mutant Strains Mice; NF-kappa B; Nitric Oxide; Oxidative Stress; PTGS2 gene; Phase; Phenethyl Isothiocyanate; Phosphorylation; Play; Prevention; Proto-Oncogene Proteins c-akt; Ptosis; Quinone Reductases; Rectum; Role; Series; Severities; Signal Pathway; Signaling Molecule; Small Intestines; Sodium Dextran Sulfate; Stress; Sulforaphane; Testing; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; cancer cell; cancer chemoprevention; carcinogenesis; cell growth; colon carcinogenesis; cytochrome c; cytokine; design; dibenzoylmethane; diketone; heme oxygenase-1; in vivo; inflammatory marker; interest; mortality; mutant; prevent; tumorigenesis

DESCRIPTION (provided by applicant): This is an R01 competing continuation application to study the mechanism of action of antioxidants [the isothiocyanates, sulforaphane (SFN) and phenethyl isothiocyanate (PEITC)] and the anti-inflammatory [the beta diketones, curcumin (CUR) and dibenzoylmethane (DBM)] effects, alone or in combination against colorectal cancer. In the last few years we have pursued the application of ITCs for the prevention of intestinal cancer in genetic APCmin/+ mice and the mechanisms of inhibition of intestinal cancer. We found that the ITCs induce a series of in vivo and in vitro effects including (1) in vivo inhibition of intestinal tumors in APCmin/+ by SFN and PEITC; (2) ITCs treatments resulted in decreased levels of inflammatory markers in the intestinal tumor, inhibition of cell survival and growth-related signaling pathways and modulation of cell cycle/apoptotic biomarkers; (3) ITCs induce apoptotic cell death via mitochondria cytochrome c release and activation of caspases in HT-29 colon cancer cells; (4) ITCs activate MAPKs leading to cell cycle arrest in HT-29 cells. In addition, we obtained preliminary data that using the Nrf2-/- mice, of which Nrf2 is known to be a transcriptional factor that plays critical role in cytoprotection against inflammation and oxidative stresses, Nrf2-deficient mice were found to be more susceptible to inflammatory agent DSS-induced colitis. The increased severity of colitis in Nrf2-/- mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes but increased in proinflammatory mediators/cytokines Furthermore, we found that PEITC protected against DSS-induced colitis in Nrf2+/+ but not in Nrf2-/- mice and that Nrf2-/- mice were more susceptible to azoxymethane (AOM)-DSS-induced colon tumors. Importantly, CUR potently protected against AOM-DSS- induced colon tumors in the Nrf2+/+ mice. Additionally, there is increasing interest and scientific rationale in the use of combinations of lower doses of chemopreventive agents possessing different mechanisms of action as a means of obtaining increased efficacy and minimized toxicity . Therefore, using our newly developed mouse colon cancer models, we would like to test our hypothesis that the antioxidants ITCs alone or in combination with anti-inflammatory CUR/DBM prevent colon cancer efficiently and safely, primarily by increasing the levels of cellular antioxidant defense enzymes and inhibition of inflammatory/pro- growth signaling molecules with three Specific Aims. Aim 1. To investigate the anti-inflammatory effect of SFN, PEITC, CUR and DBM alone or in combination using DSS-induced experimental colitis model and chemopreventive effects of these compounds against AOM/DSS-induced colorectal carcinogenesis in Nrf2+/+ and Nrf2-/- mice. Aim 2 is to investigate the role of Nrf2 in APC-mediated tumorigenesis using APCmin/+ and APC1638 mice and prevention by SFN, PEITC, CUR or DBM. Aim 3 is to examine the in vivo and in vitro mechanisms of carcinogenesis and anticarcinogenesis of critical markers/genes observed in Aims 1 and 2 that are potentially conferring protection against colorectal carcinogenesis. Colorectal cancer is the third most common and leading cause of cancer mortality in the US. This is an R01 competing application to study the mechanism of dietary phytochemicals isothiocyanates (sulforaphane and PEITC) and phenolic compounds (curcumin and DBM) alone or in combination against colorectal cancer.

描述（由申请人提供）：这是一项 R01 竞争性延续申请，旨在研究抗氧化剂 [异硫氰酸酯、萝卜硫素 (SFN) 和苯乙基异硫氰酸酯 (PEITC)] 和抗炎剂 [β二酮、姜黄素 (CUR)] 的作用机制）和二苯甲酰甲烷（DBM）]单独或组合对抗结直肠癌的作用。在过去的几年里，我们一直在研究ITCs在APCmin/+基因小鼠中预防肠癌的应用以及抑制肠癌的机制。我们发现ITCs诱导一系列体内和体外效应，包括（1）SFN和PEITC在体内抑制APCmin/+肠道肿瘤； (2) ITCs治疗导致肠道肿瘤中炎症标志物水平降低、细胞存活和生长相关信号通路受到抑制以及细胞周期/凋亡生物标志物的调节； (3) ITCs通过线粒体细胞色素c释放和激活HT-29结肠癌细胞中的caspases诱导细胞凋亡； (4) ITC 激活 MAPK，导致 HT-29 细胞的细胞周期停滞。此外，我们获得了初步数据，使用 Nrf2-/- 小鼠（已知 Nrf2 是一种转录因子，在细胞保护、抵抗炎症和氧化应激方面发挥着关键作用），发现 Nrf2 缺陷的小鼠更容易受到炎症的影响。 DSS 剂诱发的结肠炎。 Nrf2-/- 小鼠结肠炎严重程度的增加与抗氧化剂/II 相解毒酶表达的减少有关，但促炎介质/细胞因子的表达增加。此外，我们发现 PEITC 可以保护 Nrf2+/+ 小鼠免受 DSS 诱导的结肠炎，但Nrf2-/- 小鼠中没有这种情况，并且 Nrf2-/- 小鼠更容易受到氧化偶氮甲烷 (AOM)-DSS 诱导的结肠肿瘤的影响。重要的是，CUR 有效保护 Nrf2+/+ 小鼠免受 AOM-DSS 诱导的结肠肿瘤。此外，人们对使用具有不同作用机制的较低剂量的化学预防剂的组合作为获得增加的功效和最小化的毒性的手段越来越感兴趣并具有科学依据。因此，使用我们新开发的小鼠结肠癌模型，我们想检验我们的假设，即抗氧化剂 ITC 单独使用或与抗炎 CUR/DBM 联合使用，可以有效、安全地预防结肠癌，主要是通过增加细胞抗氧化防御酶的水平以及抑制炎症/促生长信号分子，具有三个具体目标。目的 1. 利用 DSS 诱导的实验性结肠炎模型研究 SFN、PEITC、CUR 和 DBM 单独或联合使用的抗炎作用以及这些化合物对 AOM/DSS 诱导的 Nrf2+/+ 和 Nrf2- 结直肠癌的化学预防作用/- 老鼠。目标 2 是使用 APCmin/+ 和 APC1638 小鼠研究 Nrf2 在 APC 介导的肿瘤发生中的作用以及通过 SFN、PEITC、CUR 或 DBM 进行预防。目标 3 是检查目标 1 和 2 中观察到的关键标记物/基因的体内和体外致癌和抗癌机制，这些标记物/基因可能具有防止结直肠癌发生的作用。结直肠癌是美国第三大常见癌症死亡原因。这是一项 R01 竞争性应用，旨在研究膳食植物化学物质异硫氰酸酯（萝卜硫素和 PEITC）和酚类化合物（姜黄素和 DBM）单独或组合抗结直肠癌的机制。