The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells
The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells
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DOI：
10.1038/sj.leu.2403828
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发表时间：
2005-08-01
期刊：
影响因子：
11.4
通讯作者：
Ruvolo, PP
中科院分区：
文献类型：
--
作者：
Konopleva, M;Contractor, R;Ruvolo, PP
开发新的治疗策略是急性髓系白血病(AML)治疗的持续挑战。新型三萜类化合物2-氰基-3，12-二氧杂环烯-1，9-二烯-28-酸的C-28甲酯(CDDO-Me)可诱导髓系白血病细胞系和原代AML样本的细胞凋亡。本研究检测了CDDO-Me对CD34(+)AML祖细胞的体外作用。CDDO-Me在10例AML样本中除1例外，其余均可诱导细胞凋亡。已知CDDO-Me可抑制ERK1/2的激活。在这一系列的原发AML样本中，所有研究的患者样本都表达并磷酸化了ERK，而CDDO-Me抑制了10例样本中的5例ERK的磷酸化。然而，CDDO-Me在不降低PERK水平的情况下诱导了五个样本中的四个，这表明PERK不是该化合物的唯一靶点。CDDO-Me诱导AML来源的U937细胞p38的磷酸化。用p38抑制剂预处理U937细胞可保护细胞免受CDDO-Me的细胞毒作用。这些发现表明p38在CDDO-Me诱导的细胞凋亡中起作用。在初步研究中，CDDO-Me在8个原发AML样本中有7个诱导p38磷酸化。这些发现表明，CDDO-Me治疗使细胞信号远离细胞保护途径，因此CDDO-Me可能是治疗AML的有效药物。
Development of novel therapeutic strategies is a continuing challenge for the treatment of acute myeloid leukemia (AML). The novel triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid (CDDO-Me), induces apoptosis in myeloid leukemic cell lines and in primary AML samples. In this report, the effects of CDDO-Me on CD34(+) AML progenitor cells in vitro were examined. CDDO-Me induced apoptosis in all but one of ten AML samples. CDDO-Me is known to inhibit the activation of ERK1/2. In this series of primary AML samples, ERK was expressed and phosphorylated in all patient samples studied and CDDO-Me inhibited ERK phosphorylation in five of 10 samples. However, CDDO-Me induced apoptosis in four of five samples without decreasing pERK levels, suggesting that pERK is not the sole target of the compound. CDDO-Me induced phosphorylation of p38 in AML-derived U937 cells. Pretreatment of U937 cells with a p38 inhibitor protected cells from the cyto-toxic effects of CDDO-Me. These findings suggest a role for p38 in CDDO-Me-induced apoptosis. In preliminary studies, CDDO-Me induced p38 phosphorylation in seven of eight primary AML samples. These findings suggest that CDDO-Me treatment shifts cell signaling away from cyto-protective pathways and thus CDDO-Me may be effective for the treatment of AML.