Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells.
Targeting PKC-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells.
复制标题
DOI：
10.1002/jcb.23090
复制
发表时间：
2011-06
影响因子：
4
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Ruvolo, Peter P.;Zhou, Liran;Watt, Julie C.;Ruvolo, Vivian R.;Burks, Jared K.;Jiffar, Tilahun;Kornblau, Steven;Konopleva, Marina;Andreeff, Michael
急性髓细胞白血病（AML）的最新研究表明，包括蛋白激酶C（PKC）介导的促增殖信号级联反应的激活代表了患者的不良预后因素。经典的PKC亚型α和β通常支持生存信号传导，并已成为抗癌治疗的重要靶点。恩扎洛宁是一种PKC β抑制剂，正在进行淋巴瘤、神经胶质瘤和肺癌的临床试验。目前，尚不清楚恩扎鲁肽是否对AML有效。在目前的研究中，我们发现高剂量的恩扎鲁肽可以促进AML衍生细胞系和AML患者的原始细胞的凋亡。然而，细胞死亡的机制可能不涉及PKC β，因为另一种PKC β抑制剂对AML细胞系没有毒性，并且不促进enzavirin诱导的细胞杀伤。虽然恩扎鲁肽对PKC β具有相当的特异性，但该药物可在较高浓度下抑制其他PKC亚型。在AML细胞系中，Enzaelatin可有效抑制PKC α磷酸化和膜定位，并抑制BCL 2的磷酸化。此外，enzavin抑制ERK的激活（其可被PKC α激活）。恩扎鲁肽处理后HL 60细胞中丝氨酸/苏氨酸磷酸化谱的分析显示，该药物抑制一组不同蛋白质的磷酸化，同时促进另一组蛋白质的磷酸化。这表明该药物可能调节多种信号通路。综上所述，这些发现表明恩扎鲁肽可有效治疗AML。
Recent studies in acute myeloid leukemia (AML) suggest activation of pro-proliferative signaling cascades including those mediated by protein kinase C (PKC) represent a poor prognostic factor for patients. The classical PKC isoforms α and β generally support survival signaling and have emerged as important targets for anti-cancer therapy. Enzastaurin is a PKC β inhibitor and is in clinical trials for lymphomas, gliomas, and lung cancer. Presently, it is not known if enzastaurin could be effective against AML. In the current study, we found that high dose enzastaurin was found to promote apoptosis in the AML-derived cell lines and in blast cells from AML patients. The mechanism of cell death, however, likely does not involve PKC β as another PKC β inhibitor was not toxic to AML cell lines and did not promote enzastaurin-induced cell killing. While enzastaurin is fairly specific for PKC β, the agent can inhibit other PKC isoforms at higher concentrations. Enzastaurin was effective at inhibiting PKC α phosphorylation and membrane localization in the AML cell lines and suppressed phosphorylation of BCL2. Furthermore, enzastaurin suppressed activation of ERK (which can be activated by PKC α). Analysis of the serine/threonine phosphorylation profile in HL60 cells after enzastaurin treatment revealed that the drug inhibits the phosphorylation of a distinct set of proteins while promoting phosphorylation of another set of proteins. This suggests the drug may regulate multiple signaling pathways. Taken together, these findings suggest that enzastaurin could be effective in the therapy of AML.
登录
查看更多内容
影响因子：
64.8
作者：
FARRAR, WL;THOMAS, TP;ANDERSON, WB
通讯作者：
ANDERSON, WB
影响因子：
20.3
作者：
Kornblau, Steven M.;Womble, Matthew;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
11.2
作者：
Graff, JR;McNulty, AM;Thornton, D
通讯作者：
Thornton, D
影响因子：
50.5
作者：
Hanauske, A. -R.;Lahn, M.;Giaccone, G.
通讯作者：
Giaccone, G.
影响因子：
11.4
作者：
MULLER, G;AYOUB, M;PFIZENMAIER, K
通讯作者：
PFIZENMAIER, K