Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice
Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice
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DOI：
10.1007/s10495-007-0116-2
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发表时间：
2007-11-01
期刊：
影响因子：
7.2
通讯作者：
Ray, Swapan K.
中科院分区：
文献类型：
--
作者：
Karmakar, Surajit;Banik, Naren L.;Ray, Swapan K.
胶质母细胞瘤是最常见和高度恶性的脑肿瘤，继续无视当前的治疗策略。本研究采用全反式维甲酸(ATRA)和紫杉醇(TXL)联合治疗人胶质母细胞瘤T98G裸鼠移植瘤。组织病理学检查显示，ATRA诱导分化，ATRA与TXL联合作用较单独用药诱导更多的细胞凋亡。联合治疗降低了端粒酶、核因子kappaB和凋亡抑制蛋白的表达，表明抑制了生存因素，而上调了Smac/DIABLO。联合治疗还改变了Bax和Bcl2蛋白的表达，导致Bax：bcl2比值升高，线粒体释放细胞色素c和凋亡诱导因子(AIF)，并激活caspase-9。钙蛋白酶和caspase-3活性的增加使特定位点的270kD的α-血影蛋白降解，分别产生145kD和120kD的血影蛋白分解产物(SBDP)。此外，caspase-3活性增加可切割caspase激活的DNA酶抑制物(ICAD)。原位双重免疫荧光标记显示，在细胞凋亡过程中，calain、caspase-12、caspase-3和AIF过表达，提示caspase依赖和不依赖于caspase的途径参与了细胞的凋亡。我们的研究揭示了ATRA和TXL联合治疗胶质母细胞瘤T98G移植瘤诱导分化和多种分子机制诱导的细胞凋亡。
Glioblastoma is the most prevalent and highly malignant brain tumor that continues to defy current treatment strategies. This investigation used all-trans retinoic acid (ATRA) and taxol (TXL) as a combination therapy for controlling the growth of human glioblastoma T98G xenografted in athymic nude mice. Histopathological examination revealed that ATRA induced differentiation and combination of ATRA and TXL caused more apoptosis than either treatment alone. Combination therapy decreased expression of telomerase, nuclear factor kappa B (NF kappa B), and inhibitor-of-apoptosis proteins (IAPs) indicating suppression of survival factors while upregulated Smac/Diablo. Combination therapy also changed expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9. Increased activities of calpain and caspase-3 degraded 270 kD alpha-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. Further, increased activity of caspase-3 cleaved inhibitor-of-caspase-activated DNase (ICAD). In situ double immunofluorescent labelings showed overexpression of calpain, caspase-12, caspase-3, and AIF during apoptosis, suggesting involvement of both caspase-dependent and caspase-independent pathways for apoptosis. Our investigation revealed that treatment of glioblastoma T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis.