Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110¦Ä subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors

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• 作者：Yan Xing^a ; ^{yxing@bccrc.ca} ; ^{xingyan2005@gmail.com} ; Donna E. Hogge^a ; ^b
• 关键词：AML ; Targeted therapy ; p110¦Ä ; MEK1/MEK2 ; Small molecule inhibitor ; PCN5603 ; U0126 ; Drug combination
• 刊名：Leukemia Research
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：37
• 期：6
• 页码：697-704
• 全文大小：1832 K

文摘

Treatment of 32 acute myeloid leukemia (AML) blast samples showing activation of the PI3K and RAS/RAF/MEK/ERK pathways with the PI3K p110¦Ä isoform and MEKinase selective inhibitors, PCN5603 and U0126 produced dose dependent progenitor kill and inhibition of p-Akt Ser473 and p-Erk Tyr204 expression. Normal marrow or blood progenitors were less sensitive to these inhibitors (median PCN5603 IC₅₀s for AML and normal cells 1.5 and 5.8 ¦ÌM and for U0126 9.6 and 25.8 ¦ÌM, respectively). U0126 synergized with PCN5603 for killing of both AML and normal progenitors. However, the synergy was less for normal than for AML cells and the median IC₅₀ of each drug in the combination 7- to 10-fold higher than for AML cells.