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

Phytother Res. 2018 Oct;32(10):2097-2104. doi: 10.1002/ptr.6156. Epub 2018 Jul 20.

Abstract

Resveratrol at high concentrations (50-100 μmol/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-μmol/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 α1 (AMPKα1) in leukemia cells. Therefore, we correlated AMPKα1 down-regulation and leukemia cell death. AMPKα1 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 AMPKα1-overexpressed leukemia cells, when compared with vector-transfected cells. Cell death was elevated by AMPKα1 overexpression, whereas pinosylvin-induced cell death was markedly decreased by caspase-3 inhibitors or autophagy inhibitors. These results suggest that pinosylvin-induced depletion of AMPKα1 enhances cell death via apoptosis and autophagy in leukemia cells.

Keywords: AMPK; LC3; apoptosis; autophagy; pinosylvin.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Caspase 3 / metabolism
  • Down-Regulation
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia / drug therapy
  • Leukemia / pathology*
  • Resveratrol
  • Stilbenes / pharmacology*
  • THP-1 Cells
  • U937 Cells

Substances

  • Stilbenes
  • pinosylvin
  • AMP-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Resveratrol

Grants and funding