Controlling tumor growth by modulating endogenous production of reactive oxygen species.
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 (H(2)O(2)), 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 H(2)O(2) is controlled by catalase. N-acetylcysteine, which decreases H(2)O(2) levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H(2)O(2) concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H(2)O(2) 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.
Laurent
Alexis
A
Laboratoire d'Immunologie and Laboratoire de Recherche Chirurgicale, Unité Propre de Recherche de l'Enseignement Supérieur 1833, Faculté Cochin, Université Paris V, 75679 Paris Cedex 14, France.
Nicco
Carole
C
Chéreau
Christiane
C
Goulvestre
Claire
C
Alexandre
Jérôme
J
Alves
Arnaud
A
Lévy
Eva
E
Goldwasser
Francois
F
Panis
Yves
Y
Soubrane
Olivier
O
Weill
Bernard
B
Batteux
Frédéric
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004347:Drug Interactions; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide