Establish the chemopreventive strategy using PPAR gamma ligands for colorectal cancer

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结合与CRC风险增加相关，则PPARY的激活可能在结肠致癌作用中发挥有益作用。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。

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.