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首页> 外文期刊>Journal of cellular biochemistry. >Sodium valproate potentiates staurosporine-induced apoptosis in neuroblastoma cells via Akt/survivin independently of HDAC inhibition
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Sodium valproate potentiates staurosporine-induced apoptosis in neuroblastoma cells via Akt/survivin independently of HDAC inhibition

机译：丙戊酸钠通过Akt / survivin增强星形胶质细胞诱导的神经母细胞瘤细胞凋亡，而不受HDAC抑制

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摘要

Sodium valproate (VPA) has been recently identified as a selective class I histone deacetylase (HDAC) inhibitor and explored for its potential as an anti-cancer agent. The anti-cancer properties of VPA are generally attributed to its HDAC inhibitory activity indicating a clear overlap of these two actions, but the underlying mechanisms of its anti-tumor effects are not clearly elucidated. The present study aimed to delineate the molecular mechanism of VPA in potentiating cytotoxic effects of anti-cancer drugs with focus on inhibition of HDAC activity. Using human neuroblastoma cell lines, SK-N-MC, SH-SY5Y, and SK-N-SH, we show that non-toxic dose (2 mM) of VPA enhanced staurosporine (STS)-induced cell death as assessed by MTT assay, PARP cleavage, hypodiploidy, and caspase 3 activity. Mechanistically, the effect of VPA was mediated by down regulation of survivin, an anti-apoptotic protein crucial in resistance to STS-mediated cytotoxicity, through Akt pathway. Knock down of class I HDAC isoforms remarkably inhibited HDAC activity comparable with that of VPA but had no effect on STS-induced apoptosis. Moreover, MS-275, a structurally distinct class I HDAC inhibitor did not affect STS-mediated apoptosis, nor decrease the levels of survivin and Akt. Valpromide (VPM), an amide analog of VPA that does not inhibit HDAC also potentiated cell death in NB cells associated with decreased survivin and Akt levels suggesting that HDAC inhibition might not be crucial for STS-induced apoptosis. The study provides new information on the possible molecular mechanism of VPA in apoptosis that can be explored in combination therapy in cancer. J. Cell. Biochem. 114: 854-863, 2013. ? 2012 Wiley Periodicals, Inc.
机译：丙戊酸钠（VPA）最近已被确定为选择性的I类组蛋白脱乙酰基酶（HDAC）抑制剂，并已探究其作为抗癌剂的潜力。 VPA的抗癌特性通常归因于其HDAC抑制活性，表明这两个作用明显重叠，但尚不清楚其抗肿瘤作用的潜在机制。本研究旨在描述VPA增强抗癌药物细胞毒性作用的分子机制，重点是抑制HDAC活性。使用人成神经细胞瘤细胞系，SK-N-MC，SH-SY5Y和SK-N-SH，我们显示无毒剂量（2 mM）的VPA增强了星形孢菌素（STS）诱导的细胞死亡，如MTT分析所评估，PARP裂解，二倍体和caspase 3活性。从机理上讲，VPA的作用是通过下调Survivin介导的，Survivin是一种抗凋亡蛋白，通过Akt途径抵抗STS介导的细胞毒性。与VPA相比，抑制I类HDAC亚型显着抑制HDAC活性，但对STS诱导的细胞凋亡没有影响。此外，MS-275，一种结构上独特的I类HDAC抑制剂，既不影响STS介导的细胞凋亡，也不降低survivin和Akt的水平。 Valpromide（VPM），一种不抑制HDAC的VPA酰胺类似物，也可增强与Survivin和Akt水平降低有关的NB细胞中的细胞死亡，提示HDAC抑制对于STS诱导的细胞凋亡可能并非至关重要。这项研究提供了有关VPA在细胞凋亡中可能的分子机制的新信息，可以在癌症的联合治疗中进行探索。 J.细胞。生化。 114：854-863，2013。 2012 Wiley期刊公司

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