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.

激活PPARY的合成配体，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。一些报道已经清楚地表明，PPARY配体可以抑制结直肠癌细胞的生长并诱导凋亡。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的风险增加有关，PPARY的激活可能在结肠癌发生中发挥有益的作用。用PPARY配体治疗CRC的临床试验结果显示，PPARY配体治疗晚期或转移性CRC的效果不佳。这意味着将PPARY作为特异性抗肿瘤靶点的目标不太可能成功，因为PPARY配体不是治疗晚期或转移性CRC的活性剂。最近，我们已经证明了PPARY配体在小鼠模型结肠癌发生的早期阶段具有显著的抑制作用，这表明PPARY配体作为癌症发生的化学预防剂具有潜在的应用前景。此外，在人体研究中，PPARY配体治疗显著减少了异常隐窝病灶（结直肠癌前病变）的数量。PPARY配体的应用具有安全性，可能作为早期结直肠癌的抗癌药物在临床上应用。这些结果表明，PPARY配体是一个有前途的候选人作为化学预防剂的CRC。

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.

Peroxisome Proliferator-Activated Receptor γ(PPARy)Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the β-Catenin/T Cell Factor(TCF) Pathway

过氧化物酶体增殖物激活受体 γ (PPARy) 通过抑制 β-连环蛋白/T 细胞因子 (TCF) 途径抑制结肠上皮细胞更新和结肠癌发生

• 发表时间: 2008
• 期刊: Journal of Pharmacological Sciences 106
• 作者: Fujisawa T;Nakajima A;Fujisawa T;Takahashi H;Ikeda I;Tomimoto A;Yonemitsu K;Nakajima N;Kudo C;Wada K;Kubota N;Terauchi Y;Kadowaki T;Nakagama H;RS Blumberg
• 通讯作者: RS Blumberg

Inhibition of peroxisome proliferators-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties.

抑制食管癌细胞中的过氧化物酶体增殖物激活受体γ活性会导致侵袭特性急剧下降。

• 发表时间: 2006
• 期刊: Cancer Sci 97(9)
• 作者: Hirokazu Takahashi;Kouji Fujita;Toshio Fujisawa;Kyoko Yonemitsu;Ayako Tomimoto;Ikuko Ikeda;Masato Yoneda;Katherine Schaefer;Lawrence J Saubermann;Takeshi Shimamura;Satoru Saitoh;Masashi Tachibana;Koichiro Wada;Hitoshi Nakagama;Atsushi Nakaji
• 通讯作者: Atsushi Nakaji

Blastocystis hominis infection in patient with regular dialysis

定期透析患者人芽囊原虫感染

• 发表时间: 2006
• 期刊: J Gastroenterol 41(6)
• 作者: Hayashi M;Inamori M;Goto K;Akiyama T;Fujita K;Ikeda I;Fujisawa T;Takahashi H;Yoneda M;Hara K;Abe Y;Kirikoshi H;Kubota K;Saito S;Ueno N;Nakajima A;Hamada Y;fukutomi H;Satsuta H
• 通讯作者: Satsuta H