title: Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors.
abstract: Treatment of 32 acute myeloid leukemia (AML) blast samples showing activation of the PI3K and RAS/RAF/MEK/ERK pathways with the PI3K p110δ 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 μM and for U0126 9.6 and 25.8 μM, 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.
authors.affiliation: Terry Fox Lab, British Columbia Cancer Agency, Vancouver, BC, Canada. yxing@bccrc.ca
authors.forename: Yan
authors.initials: Y
authors.lastname: Xing
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hogge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C482128:MAP2K2 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2