Resveratrol Suppresses Constitutive Activation of AKT via Generation of ROS and Induces Apoptosis in Diffuse Large B Cell Lymphoma Cell Lines

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.

Resveratrol Sensitizes Acute Myelogenous Leukemia Cells to Histone Deacetylase Inhibitors through Reactive Oxygen Species-Mediated Activation of the Extrinsic Apoptotic Pathway

“…In this context, resveratrol by itself induced expression of DR5 (Fig. 5A), as reported for diffuse large B-cell lymphoma cells (Hussain et al, 2011). Coadministration of LBH-589 clearly enhanced resveratrol-mediated DR5 up-regulation (Fig.…”

“…Both up-regulation of DR5 and activation of the extrinsic pathway were essentially abrogated by the ROS scavenger MnTBAP. It is interesting to note that similar phenomena were observed in human lymphoma (diffuse large B-cell lymphoma) cells exposed to resveratrol alone (Hussain et al, 2011). Together, these findings suggest that ROS-dependent induction of death receptors (e.g., DR5) and the resulting activation of the extrinsic apoptotic pathway represent an important mechanism underlying antileukemic synergism between these agents.…”

“…In this context, HDACIs are known to up-regulate death receptors in human leukemia cells (Insinga et al, 2005), and resveratrol was shown to up-regulate death receptors, including DR5, in lymphoma cells (Hussain et al, 2011). Consistent with these observations, exposure of leukemia cells to resveratrol and HDACIs increased DR5 expression, compared with the effects of each agent administrated individually.…”

“…Activation of Sirt1 decreases HDACImediated p65 acetylation and NF-B activation, which are events known to promote HDACI lethality (Dai et al, 2005). Resveratrol-mediated ROS generation, in cooperation with HDACIs (Insinga et al, 2005), triggers up-regulation of death receptors (e.g., DR5) (Hussain et al, 2011), which leads to activation of the extrinsic cascade, release of mitochondrial death proteins (e.g., cytochrome c), and full engagement of the apoptotic cascade. ROS also cause DNA damage, the lethal consequences of which may be exacerbated by HDACImediated interference with or down-regulation of DNA repair proteins (Subramanian et al, 2005;Lee et al, 2010).…”

Potential Therapeutic Molecular Targets for Nasopharyngeal Carcinoma

“…Although resveratrol is a poor ROS scavenger in vitro, it behaves as a potent anti-oxidant due to its ability to increase the synthesis of nitric oxide in vivo (22,54,96,324). During the last decade, resveratrol has been shown to have strong anti-carcinogenic activity in a wide range of human cancer cell lines, such as anaplastic large-cell lymphoma SR-786 (141), breast cancer MCF-7 and MDA-MB231 (267), chronic myeloid leukemia K562 (132), colon cancer HT-29 (298), diffuse large B cell lymphoma DLBCL (117), glioblastoma A172 and T98G (171), glioma U87 (69), hepatocellular carcinoma Huh-7 (168), leukemia HL-60 (163), leukemic monocyte lymphoma U937 (90), lung adenocarcinoma ASTC-a-1 (344), medullary thyroid cancer (291), melanoma YUZAZ6 and M14 (290), neuroblastoma B65 (236), non-small cell lung cancer A549 (188,189), and prostate cancer LNCaP cell lines (37). Resveratrol also been shown to suppress the growth of cancer in vivo such as colon (55,316), hepatocellular (13), lung (200), mammary (31), and skin cancer (82).…”