Abstract
BackgroundWe have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4′, 5-trihydroxystilbene), a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL) cells in causing inhibition of cell viability and inducing apoptosis.Methodology/Principal FindingsWe investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS). Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect.Conclusion/SignificanceAltogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.
Highlights
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoid malignancy and constitutes approximately 40% of all cases [1]
And C, Resveratrol treatment inhibited colony formation in HBL-1 cell line. These set of data clearly demonstrated that Resveratrol treatment inhibited cell viability and induced apoptosis in diffuse large B cell lymphoma (DLBCL) cell lines
We found that DLBCL cells that were transfected with scrambled non-specific siRNA showed a synergistic apoptotic response to the combination treatment; in those cells that were transfected with siRNA against Death Receptor 5 (DR5), there was a diminished apoptotic response following combination treatment of Resveratrol and Tumor necrosis factor related apoptosis inducing ligand (TRAIL) at sub-toxic doses
Summary
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoid malignancy and constitutes approximately 40% of all cases [1]. We have previously shown that PI39-kinase/AKT signaling plays a pivotal role in pathogenesis of DLBCL and other cancer cells by activating AKT and it’s down stream targets, FOXO-1, GSK-3 and Bad [4,5,6]. We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,49, 5-trihydroxystilbene), a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL) cells in causing inhibition of cell viability and inducing apoptosis
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