Bcl-2 Modulates Resveratrol-Induced ROS Production by Regulating Mitochondrial Respiration in Tumor Cells

Abstract

Resveratrol is a naturally occurring flavanoid with potent apoptosis-inducing activity against human tumor cells. We investigated the effect of resveratrol on human leukemia cell lines, in particular its ability to induce intracellular reactive oxygen species production and the effect of Bcl-2 overexpression on this model. Exposure of CEM cells to increasing concentrations of resveratrol (0-50 microM) resulted in an increase in mitochondrial superoxide production, decrease in transmembrane potential, and a concomitant decrease in cell viability. Whereas overexpression of Bcl-2 increased mitochondrial oxygen consumption and complex IV activity, CEM/Bcl-2 cells responded to the increased mitochondrial oxidative stress induced by resveratrol by significantly reducing mitochondrial respiration, complex IV activity, and O(2)(-) production, and promoted cell survival. The inhibitory effect of Bcl-2 on resveratrol-induced mitochondrial O(2)(-) production is further corroborated by the neutralization of this regulatory effect upon siRNA-mediated gene silencing of Bcl-2. These data provide evidence implicating mitochondrial metabolism in the anticancer activity of resveratrol, and underscore a novel regulatory role of Bcl-2 against exogenous oxidative stress through its ability to fine tune mitochondrial respiration, and by doing so maintaining mitochondrial O(2)(-) at a level optimal for survival.

The Effect of Resveratrol on the Quality of Extended Boar Semen During Storage at 17ºC

“…8;2013 potential than in RSV 20 µg/mL treated group (Silva et al, 2012). The decrease in the mitochondrial membrane potential caused by RSV has been widely described in somatic cells and has allowed its use in cancer treatment since RSV is able i) to regulate the mitochondrial permeability transition pore (Zunino & Storms, 2006), ii) to increase the mitochondrial superoxide production (Low et al, 2010), iii) to decrease the mitochondrial membrane potential (Sareen et al, 2006;van Ginkel et al, 2007) and iv) to disrupt the mitochondrial respiratory chain (Zheng & Ramirez, 2000;Zini et al, 1999). The ATP content diminution in RSV treated boar spermatozoa is very clear in our study, falling between 3-6 times when using 33 µM RSV and 10 to 20 times when using 100 µM RSV.…”

“…At present, a large number of studies show that the natural polyphenol resveratrol may be beneficial to many aspects of cell function and animal health; however, this compound displays a dichotomy: low doses can improve cell function while high doses increase cell death with a concomitant decrease in the mitochondrial membrane function (Fulda et al, 2010;Low et al, 2010;Pervaiz & Holme, 2009;Sareen et al, 2006;Zini et al, 1999;Zunino & Storms, 2006). Regarding male reproductive system, some studies have focused in the actions of resveratrol with divergent results (Branco et al, 2010;Collodel et al, 2011;Garcez et al, 2010;Juan et al, 2005;Ourique et al, 2013;Silva et al, 2012).…”

Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells

“…Increase of mitochondria permeability and cytochrome c release are frequently due to reactive oxygen species (ROS) [37,38] often involved in apoptosis triggered by chemopreventive agents [39]. Several studies have revealed prooxidant effects of plantderived polyphenols like flavonoids or resveratrol [39].…”

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

“…Earlier studies showed that both resveratrol (Schilder et al, 2009;Low et al, 2010) and HDACIs (Ruefli et al, 2001;Rosato et al, 2010) could trigger cell death through an oxidative injury-mediated process. Therefore, the effects of resveratrol with or without HDACIs on the generation of reactive oxygen species (ROS) were examined.…”

“…Resveratrol has been associated with minimal toxicity, and plasma levels of Ͼ300 M are achievable and well tolerated among humans (Howells et al, 2011). In preclinical studies, resveratrol exhibited activity against various malignant cell types, including AML (Tsan et al, 2002), through diverse mechanisms such as inhibition of IKK and NF-B (HolmesMcNary and Baldwin, 2000), induction of oxidative injury (Low et al, 2010), and autophagy (Puissant et al, 2010). Resveratrol was shown to act as a Sirt1 agonist (Milne et al, 2007), although evidence indicating that this may involve indirect actions has emerged (Pacholec et al, 2010).…”