Synergistic Anti-Leukemic Effect of Protein Kinase A Activator and PPARγ Agonist Is Independent of Bcl-2 Status.

The fatty acid derivate tetradecylthioacetic acid (TTA) and 8-CPT-cAMP have previously been shown to have anti-proliferative activities through activation of PPARγ and effects on the mitochondrial metabolism, respectively. Based on our previous work, we hypothesized that these two agents have a converging point of action. The combined effect of these two compounds was investigated in acute myelogenous cell lines (IPC-81 and HL-60), including IPC-81 clones over expressing either Bcl-2 or inducible cAMP early transcription repressors (ICER). Brown Norwegian rat leukaemia (BNML) was used as an in vivo model system. 8-CPT-cAMP- and TTAs anti-leukemic activity was assessed in vivo and in vitro. The compounds were able to synergistically induce a decrease in viability in promyelocytic IPC-81 cells when measured by combinational index. Enforced expression of ICER could partially protect the cell from TTA induced apoptosis. Bcl-2 over expression did not prevent additive apoptosis induction of the two compounds. An additive proliferation inhibition of the two compounds was detected in HL-60 cells at a 8-CPT-cAMP concentration that did not affect viability in itself. TTA and 8-CPT-cAMP had a spleen anti-leukaemic activity in vivo but the schedule of administration will have to be further investigated. In conclusion there seems to be a converging point in the action of 8-CPT-cAMP and TTA since they synergistically decrease in vitro viability of acute leukemic cells.