Forskolin potentiates the effects of GSKJ4 in human acute myeloid leukemia cells through Protein Kinase A pathway

Forskolin is a natural cAMP elevating agent that is emerging as one of the most promising molecules for its potential use in cancer therapy. The epigenetic marks play a relevant role in several cancer types, including in leukemia. In particular, GSKJ4 has been recently demonstrated to act as a potent proliferation inhibitor in many tumor cell lines. Due to the failure of the single agent therapy, recently the chemotherapy combination has received more attention in order to increase the therapeutic index and to reduce the side effects. In this scenario, naturally occurring molecules represent the ideal candidates to investigate cooperative responses with conventional and new antineoplastic drugs. Here, we investigate the capability of forskolin to potentiate the effects of GSKJ4 in human leukemia U937 cells. We provide evidence that forskolin markedly sensitizes GSKJ4-induced antiproliferative effects through apoptosis induction (caspase-3 activation and PARP cleavage). In addition, we demonstrate that this phenomenon is mediated by cAMP elevation and Protein Kinase A (PKA) involvement, as indicated by the use of PKA inhibitor (KT-5720). In conclusion, our findings provide initial evidence about the efficacy of forskolin/GSKJ4 combination in leukemia cells and suggest a new possible therapeutic approach for AML treatment.