title: The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells.
abstract: Acute myeloid leukaemia (AML) cells show constitutive release of several chemokines that occurs in three major clusters: (I) chemokine (C-C motif) ligand (CCL)2-4/chemokine (C-X-C motif) ligand (CXCL)1/8, (II) CCL5/CXCL9-11 and (III) CCL13/17/22/24/CXCL5. Ingenol-3-angelate (PEP005) is an activator of protein kinase C and has antileukaemic and immunostimulatory effects in AML. We investigated primary AML cells derived from 35 unselected patients and determined that PEP005 caused a dose-dependent increase in the release of chemokines from clusters I and II, including several T cell chemotactic chemokines. The release of granulocyte-macrophage colony-stimulating factor and hepatocyte growth factor was also increased. CCL2-4/CXCL1/8 release correlated with nuclear factor (NF)-kappaB expression in untreated AML cells, and PEP005-induced chemokine production was associated with further increases in the expression of the NF-kappaB subunits p50, p52 and p65. Increased DNA binding of NF-kappaB was observed during exposure to PEP005, and the specific NF-kappaB inhibitor BMS-345541 reduced constitutive chemokine release even in the presence of PEP005. Finally, PEP005 decreased expression of stem cell markers (CD117, CXCR4) and increased lineage-associated CD11b and CD14 expression. To conclude, PEP005 has a unique functional pharmacological profile in human AML. Previous studies have described proapoptotic and T cell stimulatory effects and the present study describes additional T cell chemotactic and differentiation-inducing effects.
authors.affiliation: Division for Haematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway. astrid.olsnes@med.uib.no
authors.forename: Astrid Marta
authors.initials: AM
authors.lastname: Olsnes
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ersvaer
authors.forename: Anita
authors.initials: A
authors.lastname: Ryningen
authors.forename: Kristin
authors.initials: K
authors.lastname: Paulsen
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Einar Klaeboe
authors.initials: EK
authors.lastname: Kristoffersen
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation; D018925:Chemokines / Q000276:immunology; D004224:Diterpenes / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
chemical_list: C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D018925:Chemokines; D004224:Diterpenes; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011493:Protein Kinase C