Coney Island Hospital, 2601 Ocean Parkway, Brooklyn, NY 11235, USA.
PPAR Res. 2008;2008:494161. doi: 10.1155/2008/494161.
PPARgamma is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPARgamma is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activities. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer. Most studies address agonist compounds, with substantially fewer reports on anticancer effects of PPARgamma antagonists. In cancer model systems, some effects of PPARgamma agonists were not inhibited by PPARgamma antagonists, suggesting noncanonical or PPARgamma-independent mechanisms. In addition, PPARgamma antagonists, such as T0070907 and GW9662, have exhibited antiproliferative effects on a broad range of hematopoietic and epithelial cell lines, usually with greater potency than agonists. Also, additive antiproliferative effects of combinations of agonist plus antagonist drugs were observed. Finally, there are preclinical in vivo data showing that antagonist compounds can be administered safely, with favorable metabolic effects as well as antitumor effects. Since PPARgamma antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment, it is the subject of this review.
过氧化物酶体增殖物激活受体 γ（PPARγ）是治疗 2 型糖尿病（T2DM）的治疗靶点，已被用于治疗 2 型糖尿病。由于 PPARγ 在许多造血细胞、中胚层和上皮细胞癌症中表达，因此已经测试了激动剂药物，并显示出具有临床前和临床抗癌活性。虽然已经在许多癌症类型中观察到临床前活性，但仅在脂肪肉瘤和前列腺癌的试验和 II 期试验中观察到临床活性。大多数研究都涉及激动剂化合物，而关于 PPARγ 拮抗剂的抗癌作用的报道则少得多。在癌症模型系统中，一些 PPARγ 激动剂的作用不受 PPARγ 拮抗剂的抑制，这表明存在非典型或 PPARγ 非依赖性机制。此外，PPARγ 拮抗剂，如 T0070907 和 GW9662，对广泛的造血和上皮细胞系具有抗增殖作用，通常比激动剂的作用更强。此外，还观察到激动剂加拮抗剂药物联合使用具有相加的抗增殖作用。最后，有临床前体内数据表明，拮抗剂化合物可以安全给药，具有良好的代谢作用和抗肿瘤作用。由于 PPARγ 拮抗剂代表了一类新的药物，有望成为癌症治疗的广泛适用的治疗方法，因此这是本综述的主题。
