Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1.
Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1.
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DOI：
10.1158/1078-0432.ccr-12-0770
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发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
Jing Y
中科院分区：
文献类型：
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作者：
Wang R;Liu C;Xia L;Zhao G;Gabrilove J;Waxman S;Jing Y
三氧化二砷(ATO)作为单一药物用于治疗急性早幼粒细胞白血病(APL)，毒性小，但对其他类型的恶性肿瘤尚无疗效。我们测试了联合使用乙氰酸(EA)、谷胱甘肽S转移酶P1-1(GSTP1-1)抑制剂和活性氧(ROS)诱导剂是否能将ATO的疗效扩展到APL以外。在非APL白血病细胞系和淋巴瘤细胞系中检测ATO和EA的联合凋亡效应。检测ROS、GSTP1-1、谷胱甘肽和Mcl-1在细胞凋亡中的作用。比较表达GSTP1-1和不表达GSTP1-1的细胞对这种组合的选择性反应。ATO/EA联合应用协同诱导髓系白血病和淋巴瘤细胞凋亡。这种处理产生了高水平的ROS，激活了c-jun-NH2末端激酶，减少了Mcl-1蛋白的表达。这导致线粒体跨膜电位降低，细胞色素c释放，进而激活caspase3和9。诱导表达GSTP1-1的白血病和淋巴瘤细胞的凋亡需要高浓度的EA与ATO联合使用。沉默白血病细胞中的GSTP1使其对ATO/EA诱导的细胞凋亡敏感。在一组不表达GSTP1-1的B细胞淋巴瘤中，较低浓度的EA及其更有效的衍生物乙丙烯酸丁酯降低了细胞内谷胱甘肽水平，并在与ATO联合时协同诱导细胞凋亡。缺乏GSTP1-1的B细胞淋巴瘤细胞比髓系白血病细胞对ATO/EA诱导的细胞凋亡更为敏感。
Arsenic trioxide (ATO) as a single agent is used for treatment of acute promyelocytic leukemia (APL) with minimal toxicity but therapeutic effect of ATO in other types of malignancies has not been achieved. We tested whether a combination with ethacrynic acid (EA), a glutathione S-transferase P1-1 (GSTP1-1) inhibitor and a reactive oxygen species (ROS) inducer will extend the therapeutic effect of ATO beyond APL. The combined apoptotic effects of ATO plus EA were tested in non-APL leukemia and lymphoma cell lines. The role of ROS, GSTP1-1, glutathione, and Mcl-1 in apoptosis was determined. The selective response to this combination of cells with and without GSTP1-1 expression was compared. ATO/EA combination synergistically induced apoptosis in myeloid leukemia and lymphoma cells. This treatment produced high ROS levels, activated c-jun-NH2-terminal kinase and reduced Mcl-1 protein. This led to the decrease of mitochondrial transmembrane potential, release of cytochrome c and, subsequently, to activation of caspase 3 and 9. Induction of apoptosis in leukemia and lymphoma cells expressing GSTP1-1 required that high EA concentrations be combined with ATO. Silencing of GSTP1 in leukemia cells sensitized them to ATO/EA-induced apoptosis. In a sub-group of B-cell lymphoma which do not express GSTP1-1, lower concentrations of EA and its more potent derivative, ethacrynic acid butyl-ester, decreased intracellular glutathione levels and synergistically induced apoptosis when combined with ATO. B-cell lymphoma cells lacking GSTP1-1 are more sensitive than myeloid leukemia cells to ATO/EA-induced apoptosis.