Resveratrol Inhibits Drug-Induced Apoptosis in Human Leukemia Cells by Creating an Intracellular Milieu Nonpermissive for Death Execution

Abstract

Efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol (RSV) triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the inhibitory effect on hydrogen peroxide-induced apoptosis is attributed to its antioxidant property. We provide evidence that exposure of human leukemia cells to low concentrations of RSV (4 -8 M) inhibits caspase activation, DNA fragmentation, and translocation of cytochrome c induced by hydrogen peroxide or anticancer drugs C2, vincristine, and daunorubicin. Interestingly, at these concentrations, RSV induces an increase in intracellular superoxide and inhibits drug-induced acidification. Blocking the activation of NADPH oxidase complex neutralized RSVinduced inhibition of apoptosis. Furthermore, our results implicate intracellular hydrogen peroxide as a common effector mechanism in druginduced apoptosis that is inhibited by preincubation with RSV. Interestingly, decreasing intracellular superoxide with the NADPH oxidase inhibitor diphenyliodonium reversed the inhibitory effect of RSV on drug-induced hydrogen peroxide production. These data show that low concentrations of RSV inhibit death signaling in human leukemia cells via NADPH oxidase-dependent elevation of intracellular superoxide that blocks mitochondrial hydrogen peroxide production, thereby resulting in an intracellular environment nonconducive for death execution.

Protein kinase CK2 modulates apoptosis induced by resveratrol and epigallocatechin-3-gallate in prostate cancer cells

“…We also observed that proliferation of cells at low doses of resveratrol and EGCG was associated with an upregulation of CK2 expression in tumor cells. It may be noted that proliferation of cells in the presence of low doses of resveratrol has been well documented previously (49,50). This accords with our result that overexpression of CK2 can block the apoptotic signaling of resveratrol and EGCG.…”

Resveratrol disrupts peroxynitrite-triggered mitochondrial apoptotic pathway: a role for Bcl-2

“…While most data in the literature support a pro-apoptotic role for resveratrol, several studies report anti-apoptotic actions as observed in this work [50][51][52][53]. Although the reason for these discrepancies is not completely clear, both resveratrol concentration and cell type used may be relevant factors.…”

Caspase-2 Triggers Bax-Bak-dependent and -independent Cell Death in Colon Cancer Cells Treated with Resveratrol

“…However, one recent study suggests that resveratrol can prevent hydrogen peroxide-induced apoptosis in rat pheochromocytoma cells (46). A lower concentration of resveratrol is also reported to inhibit caspase activation and release of cytochrome c induced by H 2 O 2 (47). The strong antioxidant activity of the compound is attributed for its NF-B inhibition.…”