期刊
LEUKEMIA
卷 19, 期 9, 页码 1579-1589出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2403868
关键词
leukemia; histone deacetylase inhibitors; MEK1/2 inhibitors; p21(CIP1)
资金
- NCI NIH HHS [CA72955, CA63753, CA 100866, CA88906, CA93738] Funding Source: Medline
Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA ( or sodium butyrate) and PD184352 ( or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34(+) cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34(+) bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21(CIP1), Bcr/Abl, and cyclin D-1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21(CIP1) downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据