Dossier : Superoxide dismutases: recent advances and clinical applications Differential modulation of normal and tumor cell proliferation by reactive oxygen species Carole Nicco a,b, *, Alexis Laurent a,c , Christiane Chereau a , Bernard Weill a,b , Frédéric Batteux a,b a Laboratoire d’Immunologie, UPRES 1833, Faculté de Médecine, Université Paris V,AP-HP, 75679 Paris cedex 14, France b Protexel, SAS, Paris Biotech, Faculté de Médecine, Université Paris V, 75679 Paris cedex 14, France c Service de Chirurgie Digestive, CHU de Mondor, Université Paris XII, 94010 Créteil, France Received 9 December 2004 Available online 21 March 2005 1. Introduction Reactive Oxygen Species (ROS) are physiological by- products of normal aerobic metabolism [1] that can inflict direct injuries to cells through oxidative stress. The most com- mon ROS include superoxide anions (O 2 – ), hydrogen perox- ide (H 2 O 2 ), hydroxyl radicals (HO ° ) and nitric oxide (NO). The predominant source of O 2 – is the mitochondrial electron transport chain [2,1,3], but other enzymatic systems such as NADPH oxidase [4] or xanthine oxidase [5] are also able to generate superoxide anions. Moreover, in the endoplasmic reticulum, NADPH-cytochrome P450 reductase can produce O 2 – , through the leakage of electrons, as does the NAD(P)H- cytochrome oxidase contained in the electron transport chain of the nuclear membrane. Peroxisomes also contain several H 2 O 2 -generating enzymes but only a small fraction of the H 2 O 2 produced leaves this compartment because most H 2 O 2 is detoxified locally by peroxisomal catalase. The hydroxyl radicals are formed through the Fenton or Haber–Weiss reac- tion that converts O 2 – and H 2 O 2 into HO ° in the presence of Fe 2+ or Cu + . HO ° is extremely reactive and induces severe cellular oxidative damages [6,7]. On the other hand, NO is produced constitutively by vascular endothelial cells, some neuronal cells and activated macrophages. NO, that acts as a pro-inflammatory mediator [8], can interact with O 2 – and O 2 to generate peroxynitrite anions (ONOO – ) and nitrogen oxide (NOx) that account for much of NO toxicity [9]. 2. Physiological regulation of intracellular ROS concentration Various physiological lines of defense protect normal cells from the potential damages implicated by oxidative stress. First, an elaborate system of antioxidant enzymes can detoxify the whole cascade of ROS. The molecules of the superoxide dismutase (SOD) family catalyse the conversion of O 2 – into H 2 O 2 , which is further detoxified by catalase or by enzymes of the glutathione peroxidase family using reduced GSH [10]. Three isoforms of SOD, CuZn-SOD (SOD1), Mn-SOD (SOD2) and EC-SOD (SOD3) have been identified in humans. CuZn-SOD and EC-SOD are clearly related to a common ancestor, while Mn-SOD has probably a different origin. CuZnSOD, a dimeric protein (MW 32 000), dismutes super- oxide anions generated by endoplasmic reticulum and by cyto- solic as well as membrane oxidases; the mitochondrial tet- rameric MnSOD (MW 88 000) dismutes O 2 – generated by the electron leakage occurring during oxidative phosphory- lation; the tetrameric EC-SOD (MW 135 000) is released into the extracellular space [11]. This complex enzymatic antioxidant system is completed by exogenous compounds such as amino acids (e.g., argin- ine) and vitamins (e.g., Vitamins A, C, E and b-carotene), thiols (especially glutathione), tea polyphenols and enzyme- bound minerals (e.g., selenium and zinc) [12–17]. 3. ROS overproduction = danger A physiological rate of ROS production activates cellular signalling pathways necessary to cell growth and prolifera- tion, while an excessive production of ROS, overmatching the antioxidant capacities of the cell, leads to an oxidative stress that results in metabolic disturbances and cell death. * Corresponding author. Laboratoire d’Immunologie, Pavillon Gustave Roussy, 4 ème étage A - Hôpital Cochin, 75679 Paris cedex 14, France. Tel.: +33 (0)1 44 41 25 41; fax: +33 (0)1 44 41 25 46. E-mail address: carole.nicco@cochin.univ-paris5.fr (C. Nicco). Biomedicine & Pharmacotherapy 59 (2005) 169–174 http://france.elsevier.com/direct/BIOPHA/ 0753-3322/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2005.03.009