PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.
PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.
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DOI：
10.1155/2010/207420
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发表时间：
2010
影响因子：
--
通讯作者：
Chandra J
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文献类型：
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作者：
Rivera-Del Valle N;Gao S;Miller CP;Fulbright J;Gonzales C;Sirisawad M;Steggerda S;Wheler J;Balasubramanian S;Chandra J
组蛋白脱乙酰酶抑制剂 (HDACi) 已成为一种有前景的癌症治疗新途径，许多目前正处于针对各种肿瘤类型的 I/II 期临床试验中。在本研究中，我们表明，在急性白血病细胞中，PCI-24781（一种新型的基于异羟肟酸的 HDAC 抑制剂）诱导细胞凋亡和组蛋白改变需要 caspase-8 和接头分子 Fas 相关死亡结构域 (FADD)。 PCI-24781 治疗还会导致超氧化物水平升高，其他 HDACi 也有报道存在这种情况。然而，抗氧化剂不能逆转 PCI-24781 引起的组蛋白改变，表明 ROS 的产生可能是 PCI-24781 对组蛋白 H3 产生影响的下游。总而言之，这些结果通过强调 caspase-8、FADD 和增加的超氧化物水平的作用，提供了对 PCI-24781 在白血病中诱导细胞凋亡的机制的深入了解。
Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.