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August 4, 2009: by ResveratrolNews
Frank Weinberg and Navdeep S. Chandel, researchers at Northwestern University Medical School in Chicago, provide a profound new understanding of the role of reactive oxygen species in cases of cancer.
They report that tumor cells in lab dishes impair the production of p38, an inflammatory protein, and p53, an anti-cancer gene protein, to evade apoptosis (cell death) and for tumor generation to proceed.
In the diagram provided below these researchers distinguish reactive oxygen species (free radical generation) in normal cells vs tumor cells. In normal cells, low levels of oxygen free radicals can regulate controlled proliferation and growth via cell signaling whereas with high levels of free radicals induce cell death and senescence. Cancer cells with mutations in tumor suppressor genes (p53) can evade free radical generated cell death. Cancer cells exhibit high levels of free radicals leading to uncontrolled cellular proliferation (growth by rapid multiplication).
Recently Dipak Das of the University of Connecticut showed that lower-dose resveratrol inhibits and reduces damage to the heart during a heart attack. The area of dead tissue (infarct, or fibrotic/scarred tissue is dramatically reduced), but exceptionally high-dose resveratrol induces apoptosis (cell suicide) in tumor cells, but worsens the area of scarred tissue in animals subjected to an intentional heart attack. Apoptosis is desirable in cases of cancer. Resveratrol is generally known as an antioxidant, but induces abnormal cells to die off in a programmed manner in mega-doses. Differentiation between antioxidant and oxidative properties of resveratrol depend upon dosage. The pro-oxidant effect of resveratrol was recently explained (see below). In lower doses, resveratrol slows the cell renewal cycle, giving the cell more time to repair damaged DNA and inhibiting mutations. In higher doses, resveratrol speeds up the cell cycle, accelerates mutations and cell death, which is desirable in battling malignancy.
Frank Weinberg & Navdeep S. Chandel
Cellular & Molecular Life Science, early online, August 2009
F. Weinberg, N. S. Chandel
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, IL, USA
N. S. Chandel (&) Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA
Arch Biochem Biophys. 2009 Jun 15;486(2):95-102.
Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL.
Departments of Dermatology, Columbia University Medical Center, Irving Cancer Research Center, New York, NY 10032, USA.
Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4′,5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-kappaB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-X(L). In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the antiproliferative mechanisms of resveratrol.
Biochemical Society Transactions 2007 Nov;35(Pt 5):1156-60.
de la Lastra CA, Villegas I.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain. firstname.lastname@example.org
Resveratrol (3,4′,5-trihydroxystilbene) is found in various plants, including grapes, berries and peanuts. It is also present in wines, especially red wines. During the last years, it has been the focus of numerous in vitro and in vivo studies investigating its biological attributes, which include mainly antioxidant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth-promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention. In fact, recently, it has been demonstrated that the stilbene blocks the multistep process of carcinogenesis at various stages: tumour initiation, promotion and progression. More recent results provide interesting insights into the effect of this compound on the life span of yeasts and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. Nevertheless, depending on the concentration of the phytoalexin and the cell type, it has also been shown that resveratrol can exhibit pro-oxidant properties, leading to oxidative breakage of cellular DNA in the presence of transition metal ions such as copper. Recently, it has been proposed that such a pro-oxidant action could be a common mechanism for anticancer and chemopreventive properties of plant polyphenols. The present paper is intended to provide the reader up-to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.