Evidence for peroxidative oxidation of substituted piperidine nitroxides, acting as apoptosis inducers in Yoshida Sarcoma cells in vivo.
The results presented herein clearly indicate that nitroxide derivatives--free radicals are effective as substrates for one-electron oxidation in the peroxidase cycle involving hydrogen peroxide, which have been the subject of considerable controversy. This oxidation is catalyzed enzymatically and it might occur in tumor cells (in vivo) where the level of ROS (H2O2 and O2.-) is increased. The result of this reaction involving hydrogen peroxide is the obligative formation of the oxo-ammonium cation involved in the superoxide dismutase-mimic reaction of nitroxides with superoxide and/or in reaction with H2O2 leading to superoxide formation and regeneration of the parent nitroxide molecule. The efficiency of this enzymatically catalyzed oxidation of nitroxide(s) depends on the structure of the substituent in position 4 of nitroxide ring as follows: -OCH3 > -NHCOCH3 > -NHCOCH2CH3. Notably, the reduced nitroxide salt was not substrate for peroxidatic oxidation clearly indicating the importance of the free radical moiety of the nitroxide molecule. These findings may have some relevance in the recent investigations of antioxidant properties/mechanisms of nitroxides. Based on these considerations we hypothesize that the administration of oxidizable free radical nitroxide compounds--antioxidants may be a useful strategy in the treatment and investigations of cancer diseases. An in vivo study ("Screening test of chemicals employing Yoshida Sarcoma animals") was carried out to verify whether the structure and/or the chain length of substituent of oxidizable nitroxide derivatives--antioxidants could influence their apoptotic activity. The results reported in this study are encouraging as we found a limited correlation between the molecular oxidative properties of nitroxides under study, their structure and antitumor (apoptotic) action. In conclusion, this work demonstrates that investigation of the structure-dependent oxidation of antioxidatively acting nitroxides can become a very important step in their future screening and selection for applications in vivo and in vitro.
Metodiewa
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D
Institute of Applied Radiation Chemistry, Technical University of Lódz, Poland. media@mitr.p.lodz.pl
Kochman
A
A
Gebicka
L
L
Skolimowski
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D010084:Oxidation-Reduction; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012517:Sarcoma, Yoshida / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010880:Piperidines