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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Laboratoire d'Immunologie and 2 Laboratoire de Recherche Chirurgicale, Unité Propre de Recherche de l'Enseignement Supérieur 1833, Faculté Cochin, Université Paris V; 3 Service d'Oncologie Médicale, Hôpital Cochin; 4 Service de Chirurgie Digestive, Centre Hospitalier Universitaire Lariboisière, Université Paris VII, Paris, France; and 5 Service de Chirurgie Digestive, Centre Hospitalier Universitaire Henri-Mondor, Université Paris XII, Créteil, France
Requests for reprints: Frédéric Batteux, Laboratoire d'Immunologie, Pavillon Hardy, Hôpital Cochin, 75679 Paris cedex 14, France. Phone: 33-1-58-41-20-07; Fax: 33-1-58-41-20-08; E-mail: frederic.batteux{at}cch.ap-hop-paris.fr.
Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H2O2), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H2O2 is controlled by catalase. N-acetylcysteine, which decreases H2O2 levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H2O2 concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H2O2 levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.
Key Words: reactive oxygen species • cancer • apoptosis • antioxidant molecule • chemotherapy
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