Resveratrol-induced cell death in leukaemia cells: The effect of Hsp72 expression and combination treatments with TRAIL and ethanol

Abstract

Resveratrol, a natural phytoalexin found in grapes and red wine, displays anti-cancer activities through a variety of mechanisms that include the induction of cancer cell apoptosis. Although high concentrations may be needed for the efficacy of resveratrol alone, the compound shows promise as a potent sensitizer of the apoptotic effect of other anti-cancer agents, including death ligand TRAIL. Intracellular heat shock proteins (Hsps) are frequently up-regulated in cancer cells, conferring resistance to apoptosis. Modulation of these proteins may overcome the resistance and increase efficacy of anticancer therapies. In this study, resveratrol caused significant dose-dependent apoptosis or necrosis in the lymphoid and myeloid leukaemia cell lines Jurkat and U937 at 50µM and above. Combination treatments with sub-lethal concentrations of ethanol or TRAIL showed synergistic effects on the dose-dependent cell death, such that significant apoptosis was achieved at 25µM resveratrol. Treatment with all compounds together showed the greatest efficacy with significant apoptosis occurring at 12.5µM resveratrol, but also greater toxicity demonstrated by a shift from apoptosis to necrosis occurring at 25-50µM as opposed to 100-200µM resveratrol in the other combination treatments. Low concentrations of resveratrol that were unable to induce apoptosis caused a significant increase in intracellular Hsp72, whilst intracellular Hsp72 was unchanged or reduced at higher concentrations. Increasing intracellular Hsp72 expression in cells with a mild heat shock prior to resveratrol treatment caused increased resistance to resveratrol-induced cell death at 50-200µM. It was not possible to show that lowering intracellular Hsp72 with ethanol treatment increased sensitivity to resveratrol-induced cell death. It was shown for the first time that resveratrol increased surface expression of Hsp72 at all concentrations, highlighting the potential for an additional anti-cancer effect in situ. The results indicate that combination treatments with resveratrol are promising for use in anticancer therapy, and manipulation of intracellular Hsp72 expression may modulate the efficacy of resveratrol-induced apoptosis. Further investigations are recommended into the clinical relevance of resveratrol, further synergistic compounds, and the effects of reducing intracellular and increasing surface Hsp72 levels.