Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor γ agonist treatment
Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor γ agonist treatment
复制标题
DOI：
10.1124/mol.106.022194
复制
发表时间：
2006-11-01
影响因子：
3.6
通讯作者：
Heneka, Michael T.
中科院分区：
文献类型：
--
作者：
Grommes, Christian;Landreth, Gary E.;Heneka, Michael T.
过氧化物酶体增殖物激活受体γ（peroxisomeproliferator-activatedreceptor gamma，PPARgamma）是核激素受体家族的一员，是胶质瘤治疗的新靶点。由于PPARgamma在调节胰岛素敏感性中起着至关重要的作用，合成激动剂已经在临床上用于II型糖尿病的治疗。除了这些代谢作用外，PPAR γ激动剂还表现出抑制作用。在这项研究中，我们研究了PPAR γ激动剂吡格列酮对胶质瘤细胞的抑制作用。吡格列酮在体外以时间和浓度依赖性方式降低大鼠、人和过表达PPAR γ的胶质瘤细胞的细胞活力。吡格列酮在过表达PPAR γ突变体的神经胶质瘤细胞中未诱导抑制作用。此外，通过Ki-67免疫反应性测定，体外吡格列酮可降低增殖。通过纹状体内注射C6细胞诱导的脑胶质瘤持续脑内灌注吡格列酮可使肿瘤体积减少83%。口服吡格列酮可使肿瘤体积缩小76.9%。随后的脑组织分析显示诱导凋亡性细胞死亡。Ki-67表达和BrdU掺入显示体内增殖减少。体内C6细胞侵袭性降低和基质金属蛋白酶9水平降低表明吡格列酮介导的侵袭性降低。总之，这些数据表明吡格列酮可能用于治疗恶性胶质瘤。
The peroxisome proliferator- activated receptor gamma (PPAR gamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPAR gamma plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPAR gamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPAR gamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPAR gamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPAR gamma mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83%. Oral administration of pioglitazone reduced tumor volumes by 76.9%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.