Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage.
Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage.
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DOI：
10.1002/mc.21835
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发表时间：
2013-02
影响因子：
4.6
通讯作者：
Pollack, Ian F.
中科院分区：
文献类型：
--
作者：
Premkumar, Daniel R.;Jane, Esther P.;Agostino, Naomi R.;DiDomenico, Joseph D.;Pollack, Ian F.
胶质母细胞瘤是侵袭性肿瘤，尽管目前的治疗方法预后较差。组蛋白去乙酰化酶抑制剂（HDACIs）是一类可以调节基因表达以减少肿瘤生长的药物，我们和其他人已经注意到HDACIs具有抗胶质瘤活性，如vorinostat，尽管不足以保证作为单一治疗使用。我们最近的研究表明，蛋白酶体抑制剂，如硼替佐米，可以显著地使高度耐药的胶质瘤细胞对凋亡诱导敏感，这表明蛋白酶体抑制可能是一种有希望的胶质瘤治疗联合策略。在这项研究中，我们研究了硼替佐米是否可以增强胶质瘤细胞对HDAC抑制的反应。虽然来自多形性胶质母细胞瘤（GBM）患者和已建立的胶质瘤细胞系的原代细胞在vorinostat单独治疗下没有明显诱导细胞凋亡，但vorino-stat联合硼替佐米可显著增强细胞凋亡。增强的疗效是由于凋亡前线粒体损伤和活性氧的产生增加。我们的研究结果还显示，硼替佐米联合伏立诺他通过增加Mcl-1的切割、Noxa的上调、Bak和Bax的激活以及细胞色素c的释放来促进细胞凋亡。使用shRNA进一步下调Mcl-1可增强硼替佐米/伏立诺他联合对细胞的杀伤作用。Vorinostat诱导原代GBM和T98G细胞中组蛋白H2AX的快速持续磷酸化，并且与硼替佐米联合使用可显著增强这一作用。伏立诺他/硼替佐米联合用药还可诱导Rad51下调，Rad51在DNA损伤和细胞凋亡的协同增强中起重要作用。硼替佐米和HDACIs联合使用的抗肿瘤活性显著增强，为胶质瘤患者提供了一种新的治疗方法。
Glioblastomas are invasive tumors with poor prognosis despite current therapies. Histone deacetylase inhibitors (HDACIs) represent a class of agents that can modulate gene expression to reduce tumor growth, and we and others have noted some antiglioma activity from HDACIs, such as vorinostat, although insufficient to warrant use as mono-therapy. We have recently demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics. In this study, we examined whether bortezomib could enhance response to HDAC inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with vorinostat treatment alone, the combination of vorino-stat plus bortezomib significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib with vorinostat enhanced apoptosis by increasing Mcl-1 cleavage, Noxa upregulation, Bak and Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/vorinostat combination. Vorinostat induced a rapid and sustained phosphorylation of histone H2AX in primary GBM and T98G cells, and this effect was significantly enhanced by co-administration of bortezomib. Vorinostat/bortezomib combination also induced Rad51 downregulation, which plays an important role in the synergistic enhancement of DNA damage and apoptosis. The significantly enhanced antitumor activity that results from the combination of bortezomib and HDACIs offers promise as a novel treatment for glioma patients.
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影响因子：
9.7
作者：
Jane, Esther P.;Premkumar, Daniel R.;Pollack, Ian F.
通讯作者：
Pollack, Ian F.
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
11.4
作者：
Lucas, DM;Davis, ME;Grever, MR
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Grever, MR
影响因子：
11.2
作者：
Marcus, AI;Zhou, J;Giannakakou, P
通讯作者：
Giannakakou, P
影响因子：
8
作者：
Burgess, A;Ruefli, A;Gabrielli, B
通讯作者：
Gabrielli, B