The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells.
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.
Olsnes
Astrid Marta
AM
Division for Haematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway. astrid.olsnes@med.uib.no
Ersvaer
Elisabeth
E
Ryningen
Anita
A
Paulsen
Kristin
K
Hampson
Peter
P
Lord
Janet M
JM
Gjertsen
Bjørn Tore
BT
Kristoffersen
Einar Klaeboe
EK
Bruserud
Øystein
Ø
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
C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D018925:Chemokines; D004224:Diterpenes; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011493:Protein Kinase C