Establish the chemopreventive strategy using PPAR gamma ligands for colorectal cancer

建立使用 PPAR γ 配体治疗结直肠癌的化学预防策略

• 批准号: 18390222
• 负责人: NAKAJIMA Atsushi
• 金额: $ 10.95万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390222/
• 关键词: Chemoprevention; Nuclear receptor; Colorectal Cancer; PPARγ; 大腸癌; アディポネクチン

Activating synthetic ligands for PPARY, such as pioglitazone and rosiglitazone, are commonly used to treat patients with diabetes mellitus (DM) in order to improve insulin resistance. Several reports have clearly demonstrated that PPARY ligands, could inhibit colorectal cancer cell growth and induce apoptosis. On the other hands, the insulin resistance or hyper insulinemia are thought to be the one of the major risk factors of colorectal cancer (CRC). If hyper insulinemia, alone or in combination with other features of the insulin resistance syndrome, is associated with increased risk of CRC, activation of PPARY may play a benefited role in colon carcinogenesis. The results of clinical trials for CRC with PPARY ligands have shown modest This implies that aiming at PPARY as a specific anti-tumor target is not likely to be successful, because PPARY ligands are not an active agent for the treatment of advanced or metastatic CRC. Recently, we have demonstrated the substantial suppressive effects of PPARY ligands on colon carcinogenesis in mouse model in the early stage of carcinogenesis, suggesting a potential application as the chemopreventive agents against carcinogenesis. Furthermore, number of aberrant crypt foci, pre cancerous lesion of colorectal, was significantly decreased by PPARY ligand treatment in human study. PPARY ligands are used with safety benefit and may be a clinical application as anti-cancer drug in early stage of CRC. These results suggest that PPARY ligand is a promising candidate as a chemopreventive agent for CRC.

PPARY 的激活合成配体，例如吡格列酮和罗格列酮，通常用于治疗糖尿病 (DM) 患者，以改善胰岛素抵抗。一些报告已经清楚地证明 PPARY 配体可以抑制结直肠癌细胞的生长并诱导细胞凋亡。另一方面，胰岛素抵抗或高胰岛素血症被认为是结直肠癌（CRC）的主要危险因素之一。如果高胰岛素血症单独或与胰岛素抵抗综合征的其他特征相结合，与 CRC 风险增加相关，那么 PPARY 的激活可能在结肠癌发生中发挥有益作用。 PPARY 配体对 CRC 的临床试验结果显示效果不大。这意味着将 PPARY 作为特定抗肿瘤靶点不太可能成功，因为 PPARY 配体不是治疗晚期或转移性 CRC 的活性药物。最近，我们在小鼠模型的结肠癌发生的早期阶段证明了PPARY配体对结肠癌发生的显着抑制作用，表明其作为癌症化学预防剂的潜在应用。此外，在人体研究中，PPARY 配体治疗显着减少了异常隐窝病灶（结直肠癌前病变）的数量。 PPARY配体的使用具有安全性，可能作为结直肠癌早期的抗癌药物进行临床应用。这些结果表明 PPARY 配体是作为 CRC 化学预防剂的有前途的候选者。

项目成果

PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma,PPARdelta and proteasome-independent mechanism,resulting in cell cycle arrest,apoptosis and reduced metas tasis of colorectal carcinoma cells

PPARγ抑制剂通过PPARγ、PPARδ和蛋白酶体独立机制降低微管蛋白水平，导致结直肠癌细胞的细胞周期阻滞、凋亡和转移减少

• 发表时间: 2007
• 期刊: Int J Cancer 120(3)
• 作者: Schaefer KL;Takahashi H;Morales VM;Harris G;Barton S;Osawa E;Nakajima A;Saubermann LJ
• 通讯作者: Saubermann LJ

Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation

• DOI: 10.1096/fj.06-5809com
• 发表时间: 2006-09-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Wada, Koichiro;Arita, Makoto;Serhan, Charles N.
• 通讯作者: Serhan, Charles N.

5-aminosalicylic acid given in the remission stage of colitis suppresses colitis-associated cancer in a mouse colitis model

• DOI: 10.1158/1078-0432.ccr-07-1208
• 发表时间: 2007-11-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Ikeda, Ikuko;Tomimoto, Ayako;Nakajima, Atsushi
• 通讯作者: Nakajima, Atsushi

Adipocytokines and dysplastic aberrant crypt foci.

脂肪细胞因子和发育异常的异常隐窝病灶。

• 发表时间: 2007
• 作者: Takahashi H;Yoneda K;Iida H. Tomimoto A;Endo H;Inamori M;Abe Y;Nakajima A
• 通讯作者: Nakajima A

SHP1 Phosphatase-Dependent T Cell Inhibition by CEACAMl Adhesion Molocule Isoforms

CEACAM1粘附分子亚型对SHP1磷酸酶依赖性T细胞的抑制

• 发表时间: 2006
• 期刊: Immunity 209(Pt22)
• 作者: Nagaishi T;Pao L;Lin SH;Iijima H;Kaser A Qiao SW;Chen Z;Glickman J;Najjar SM;Nakajima A;Neel BG;Blumberg RS
• 通讯作者: Blumberg RS