组蛋白去乙酰化酶抑制剂（HDACI）PCI-24781 增强阿霉素在骨肉瘤细胞中的细胞毒性作用。

Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells.

机构信息

Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

出版信息

Cancer Chemother Pharmacol. 2011 Feb;67(2):439-46. doi: 10.1007/s00280-010-1344-7. Epub 2010 May 12.

DOI:10.1007/s00280-010-1344-7

PMID:20461381

Abstract

PURPOSE

To better understand the mechanisms of cytotoxicity and cell death induced by HDACI PCI-24781 in bone sarcoma cells.

METHODS

Four bone sarcoma cell lines were treated with PCI-24781, and the cytotoxicity was investigated. Further, accumulation of acetylated histones, p21, and PARP cleavage were evaluated in PCI-24781-treated cells. The synergistic effect of PCI-24781 to doxorubicin and its mechanism was investigated in bone sarcoma cells.

RESULTS

MTT assay demonstrated that the growth of bone sarcoma cells was inhibited after treatment with PCI-24781. Accumulation of acetylated histones, p21, and PARP cleavage were found in PCI-24781-treated cells. Expression of DNA repair protein RAD51 was inhibited, and the expression of apoptosis protein GADD45α was induced by PCI-24781 in bone sarcoma cells. Bone sarcoma cells treated with PCI-24781 become more sensitive to doxorubicin. The caspase-3/7 activity was increased with doxorubicin and PCI-24781 treatment in these cells.

CONCLUSIONS

HDACI PCI-24781 has a synergistic effect on doxorubicin-induced apoptosis in bone sarcoma cells.

摘要

目的

深入了解组蛋白去乙酰化酶抑制剂 PCI-24781 在骨肉瘤细胞中诱导细胞毒性和细胞死亡的机制。

方法

用 PCI-24781 处理四种骨肉瘤细胞系，并检测其细胞毒性。进一步评估 PCI-24781 处理细胞中乙酰化组蛋白、p21 和 PARP 切割的积累情况。研究了 PCI-24781 与阿霉素联合应用的协同作用及其在骨肉瘤细胞中的机制。

结果

MTT 检测表明，PCI-24781 处理后骨肉瘤细胞的生长受到抑制。在 PCI-24781 处理的细胞中发现乙酰化组蛋白、p21 和 PARP 切割的积累。DNA 修复蛋白 RAD51 的表达受到抑制，而凋亡蛋白 GADD45α 的表达则被 PCI-24781 诱导。经 PCI-24781 处理的骨肉瘤细胞对阿霉素更加敏感。这些细胞中，caspase-3/7 活性随着阿霉素和 PCI-24781 的处理而增加。