The protein kinase C agonist PEP005 increases NF-κB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells

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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)-κB expression in untreated AML cells, and PEP005-induced chemokine production was associated with further increases in the expression of the NF-κB subunits p50, p52 and p65. Increased DNA binding of NF-κB was observed during exposure to PEP005, and the specific NF-κB 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.

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