Pinosylvin enhances leukemia cell death via down-regulation of AMPK expression

Resveratrol at high concentrations (50-100mol/L) is known to induce cell death in leukemia cells. Here, we investigated whether pinosylvin, a resveratrol analogue, induced cell death in leukemia cells. Cell death was found to be markedly elevated by 50- to 100-mol/L pinosylvin in THP-1 and U937 cells. It was also shown that pinosylvin induced caspase-3 activation, flip-flop of phosphatidylserine, LC3-II accumulation, LC3 puncta, and p62 degradation in both THP-1 and U937 cells. These data indicate that pinosylvin-induced cell death may occur through apoptosis and autophagy. In addition, we showed that pinosylvin down-regulates AMP-activated protein kinase 1 (AMPK1) in leukemia cells. Therefore, we correlated AMPK1 down-regulation and leukemia cell death. AMPK1 inhibition appeared to decrease pinosylvin-induced apoptosis and autophagy in leukemia cells, implying that AMPK is a key regulator of leukemia cell death. Moreover, we found that both pinosylvin-induced autophagy and apoptotic progress were reduced in AMPK1-overexpressed leukemia cells, when compared with vector-transfected cells. Cell death was elevated by AMPK1 overexpression, whereas pinosylvin-induced cell death was markedly decreased by caspase-3 inhibitors or autophagy inhibitors. These results suggest that pinosylvin-induced depletion of AMPK1 enhances cell death via apoptosis and autophagy in leukemia cells.