title: PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC.
abstract: Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal CD34+ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for antileukemic therapies. Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005.
authors.affiliation: MRC Centre for Immune Regulation, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Hema
authors.initials: H
authors.lastname: Chahal
authors.forename: Farhat
authors.initials: F
authors.lastname: Khanim
authors.forename: Rachel
authors.initials: R
authors.lastname: Hayden
authors.forename: Anneke
authors.initials: A
authors.lastname: Mulder
authors.forename: Lakhvir Kaur
authors.initials: LK
authors.lastname: Assi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bunce
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004952:Esters / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D011379:Prognosis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics; D051745:Protein Kinase C-delta; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C486592:3-ingenyl angelate; D004224:Diterpenes; D004791:Enzyme Inhibitors; D004952:Esters; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta