Reductive activation of mitomycins A and C by vitamin C |
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| Institution: | 1. State Key Laboratory of Metastable Materials Science and Technology, College of Materials Science and Engineering, Yanshan University, Qinhuangdao 066004, PR China;2. College of Physics and Chemistry, Henan Polytechnic University, Jiaozuo, Henan 454000, PR China;1. School of Materials Science and Nanotechnology, Jadavpur University, Kolkata 700032, India;2. Thin Film and Nanoscience Laboratory, Department of Physics, Jadavpur University, Kolkata 700032, India;1. Shandong Province Key Laboratory of Laser Polarization and Information Technology, School of Physics and Engineering, Qufu Normal University, 273165 Qufu, People''s Republic of China;2. State Key Laboratory of Functional Materials for Informatics, Laboratory of Nanotechnology, Shanghai Institute of Micro-system and Information Technology, Chinese Academy of Sciences, 200050 Shanghai, People''s Republic of China;3. National Laboratory of Solid State Microstructures, Nanjing University, Nanjing 210093, People''s Republic of China;1. College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China;2. Department of Chemistry, Fuzhou University, Fuzhou, Fujian, 350108, China;3. State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou, Fujian, 350002, China;1. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People''s Republic of China;2. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, People''s Republic of China |
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| Abstract: | The anticancer drug mitomycin C produces cytotoxic effects after being converted to a highly reactive bis-electrophile by a reductive activation, a reaction that a number of 1-electron or 2-electron oxidoreductase enzymes can perform in cells. Several reports in the literature indicate that ascorbic acid can modulate the cytotoxic effects of mitomycin C, either potentiating or inhibiting its effects. As ascorbic acid is a reducing agent that is known to be able to reduce quinones, it could be possible that the observed modulatory effects are a consequence of a direct redox reduction between mitomycin C and ascorbate. To determine if this is the case, the reaction between mitomycin C and ascorbate was studied using UV/Vis spectroscopy and LC/MS. We also studied the reaction of ascorbate with mitomycin A, a highly toxic member of the mitomycin family with a higher redox potential than mitomycin C. We found that ascorbate is capable to reduce mitomycin A efficiently, but it reduces mitomycin C rather inefficiently. The mechanisms of activation have been elucidated based on the kinetics of the reduction and on the analysis of the mitosene derivatives formed after the reaction. We found that the activation occurs by the interplay of three different mechanisms that contribute differently, depending on the pH of the reaction. As the reduction of mitomycin C by ascorbate is rather inefficiently at physiologically relevant pH values we conclude that the modulatory effect of ascorbate on the cytotoxicity of mitomycin C is not the result of a direct redox reaction and therefore this modulation must be the consequence of other biochemical mechanisms. |
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| Keywords: | Anticancer drugs Mitomycin C Bioreductive drugs Quinones Ascorbic acid |
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