Resveratrol, a tumor‐suppressive compound from grapes, induces apoptosis via a novel mitochondrial pathway controlled by Bcl‐2

Abstract

We report that resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other plant food, induced a breakdown of the mitochondrial transmembrane potential (∆Ψ m ) in T-acute lymphoblastic leukemia cells and swelling of isolated rat mitochondria. The breakdown of ∆Ψ m was accompanied by the production of reactive oxygen species (ROS), and preceded phosphatidylserine exposure and DNA fragmentation. Breakdown of ∆Ψ m was not caused by the activation of caspase-8 or Bid, as no significant cleavage of these proteins could be detected in the induction phase of resveratrol-induced apoptosis. Though loss of ∆Ψ m was not followed by cytochrome c translocation to the cytosol, the mitochondrial changes triggered significant activation of caspase-9, -2, -3, and -6. Inhibition of ∆Ψ m breakdown and of ROS generation by N-acetylcysteine, or by overexpression of Bcl-2 protein, prevented apoptosis induction by resveratrol. The Bcl-2 expression status of tumor cells should therefore be considered relevant for potential clinical application of resveratrol as anticancer agent.Key words: cell death • antioxidant • cytochrome c-independent • lymphoblastic leukemia esveratrol, a polyphenolic compound present in grapes and in red wine, has been found to inhibit cellular events that increase the risk of carcinogenesis, a finding that has initiated numerous studies on its molecular mechanisms. These studies revealed antioxidant activities such as the inhibition of free radical formation following TPA stimulation (1) and of peroxidation of lipids in microsomes and of plasma LDL (2). Further mechanisms of action comprise modulation of lipoprotein metabolism and inhibition of platelet aggregation and coagulation (3). Its chemopreventive properties have been demonstrated in vitro, where R resveratrol lowers the mutagenic responses induced in salmonella by the aryl hydrocarbon dimethylbenz[a]anthracene treatment and induces quinone reductase activity (an enzyme capable of detoxifying carcinogens) (4). Moreover, it strongly inhibits P450-1A1 activity (an enzyme that transforms environmental toxins and procarcinogens into ultimate carcinogens), and it prevents dioxin toxicity by antagonistic activity on the aryl hydrocarbon receptor (5).More recently, its antioxidant and chemopreventive effects have been demonstrated in vivo by showing that it prevents the development of preneoplastic lesions in carcinogen-treated mouse mammary glands and inhibits tumorigenesis in a mouse skin cancer model (6). These results may be explained by its growth-inhibitory effects on tumor cell lines; by its capacity to directly induce apoptosis in various human tumor models, including promyelocytic leukemia (7), prostate cancer (8), and breast cancer (9, 10); and by its tumor specificity, because it does not affect human peripheral blood lymphocytes from healthy donors (9). The growth-inhibitory effect of resveratrol might result from its influence on the expression levels or phosphorylation status of cell cycle regulators such as cyclin E, c...

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

“…Particularly, by acting as antioxidant, anti-mutagen as well as by inducing phase II drug-metabolizing enzymes, trans-resveratrol inhibits the initiation phase of tumorigenesis; concomitantly, it mediates the anti-inflammatory response and induces cell differentiation, thereby inhibiting tumor promotion and progression, respectively [28]. Subsequently, other groups reported the anti-proliferative and pro-apoptotic activity of trans-resveratrol in several tumor cell lines [2,27,41,56], suggesting that it can function by modulating and interacting with a broad range of cellular targets, ranging from cell surface receptors [5,7] to caspases [43]; from mitochondria [8] and mitochondria-associated proteins [43,50,60], to intracellular protein kinases, such as protein kinase B (PKB)/Akt, PKC, MAP kinases [34,57,58,62,65] and transcription factors (e.g. p53, pRb, c-Jun and NF-jB) [30,37,45,59].…”

Resveratrol-induced Apoptosis Is Associated with Fas Redistribution in the Rafts and the Formation of a Death-inducing Signaling Complex in Colon Cancer Cells

“…The pro-apoptotic members of the Bcl-2 family known as BH3-only proteins behave as sensors of cellular damage and initiate the death process by either inhibiting anti-apoptotic members of the family or activating another group of proapoptotic, Bcl-2-related proteins, the Bax/Bak proteins, through induction of conformational changes (14). Various reports have shown that resveratrol could induce apoptosis of tumor cells through a mitochondrial-dependent pathway that partially depended on Bax conformational changes and cellular redistribution (15)(16)(17)(18).…”

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

“…It is expected that modulators of apoptosis with different mechanisms of action independent of the classical apoptotic signaling cascade may have promising features of bypassing clinical drug resistance caused by impaired apoptotic signaling. Indeed, there are reports of cytochrome c-independent cell death induced by resveratrol that is not completely prevented by Bax deficiency, suggesting the complex nature of death signaling induced by resveratrol (25,26). Processing of caspases independent of cytochrome c in certain cellular systems (25) and marked caspase-8 activation independent of classical death receptors (27, 28) add more credibility to the notion that resveratrol-mediated apoptosis involves more complex signaling events than the conventional pathways of apoptosis triggered by other known antitumor agents.…”