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...

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Bibliographic Details
Published in:British journal of haematology 2009-06, Vol.145 (6), p.761-774
Main Authors: Olsnes, Astrid Marta, Ersvaer, Elisabeth, Ryningen, Anita, Paulsen, Kristin, Hampson, Peter, Lord, Janet M, Gjertsen, Bjørn Tore, Kristoffersen, Einar Klaeboe, Bruserud, Øystein
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents - therapeutic use
Cell Differentiation
Chemokines - immunology
Diterpenes - therapeutic use
Female
Flow Cytometry
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - immunology
Leukemia, Myeloid, Acute - metabolism
Male
Middle Aged
NF-kappa B - analysis
NF-kappa B - genetics
NF-kappa B - metabolism
Protein Kinase C - metabolism
RNA Interference
RNA, Small Interfering - pharmacology
Statistics, Nonparametric
Tumor Cells, Cultured
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Summary: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.
ISSN:1365-2141
DOI:10.1111/j.1365-2141.2009.07691.x