Active oxygen induced DNA strand breakage and poly ADP-ribosylation in promotable and non-promotable JB6 mouse epidermal cells.
The evidence is convincing that oxidants and agents which induce a cellular pro-oxidant state can act as carcinogens, in particular as promoters and progressors. Importantly, infiltrated phagocytes represent a source of oxidants in inflamed tissues. We have studied the mechanism of the promotional action of active oxygen (AO) in mouse epidermal cells JB6 by comparing the non-promotable clone 30 to the promotable clone 41. In order to mimick AO released by phagocytes we used xanthine/xanthine oxidase as a source of extracellular superoxide and hydrogen peroxide. We found that AO stimulated the growth only of promotable clone 41 after an initial period of moderate inhibition while it was strongly cytostatic for non-promotable clone 30. Reasons for the higher cytostatic effect of AO on the non-promotable clone 30 were discovered when we measured DNA strand breakage and poly ADP-ribosylation of chromosomal proteins. At equal doses AO induced 4-5 times more DNA breaks in clone 30 in reactions which required iron--and probably also calcium--ions. The higher amount of DNA breakage in clone 30 was reflected in a higher extent of poly ADP-ribosylation. Excessive DNA breakage and poly ADP-ribosylation which causes the depletion of NAD and ATP may be responsible for the strong cytostatic effect of AO in clone 30. We conclude that differential resistance to the cytostatic/cytotoxic effect of AO in part determines the promotability of mouse epidermal cells JB6.
Muehlematter
D
D
Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Epalinges/Lausanne.
Larsson
R
R
Cerutti
P
P
D000818:Animals; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003043:Cocarcinogenesis; D004249:DNA Damage; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*
D002273:Carcinogens; D009702:Nucleoside Diphosphate Sugars; D011064:Poly Adenosine Diphosphate Ribose; D010100:Oxygen