Protein kinase A activators and the pan-PPAR agonist tetradecylthioacetic acid elicit synergistic anti-leukaemic effects in AML through CREB.
Targeting of signal transduction pathways and transcriptional regulation represents an attractive approach for less toxic anti-leukaemic therapy. We combined protein kinase A (PKA) activation with a pan-peroxisome proliferator-activated receptor (PPAR) activator tetradecylthioacetic acid, resulting in synergistic decrease in viability of AML cell lines. PKA isoform II activation appeared to be involved in inhibition of proliferation but not induction of apoptosis in HL-60 cells. Inhibition of CREB function protected against this anti-leukaemic effect with higher efficiency than enforced Bcl-2 expression. Preclinical studies employing the rat AML model Brown Norwegian Myeloid Leukaemia also indicated anti-leukaemic activity of the combination therapy in vivo. In conclusion, combined PKA and pan-PPAR activation should be explored further to determine its therapeutic potential.
Erikstein
Bjarte Skoe
BS
Institute of Medicine, Haematology Section, University of Bergen, Bergen, Norway.
McCormack
Emmet
E
Tronstad
Karl Johan
KJ
Schwede
Frank
F
Berge
Rolf
R
Gjertsen
Bjørn Tore
BT
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004357:Drug Synergism; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D051381:Rats; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*
D017362:Cyclic AMP Response Element-Binding Protein; D020536:Enzyme Activators; D047492:Peroxisome Proliferator-Activated Receptors; D013440:Sulfides; C062078:1-(carboxymethylthio)tetradecane; D017868:Cyclic AMP-Dependent Protein Kinases