Cationic Mn Porphyrins Change Their Action from anti- to pro-oxidative in the Presence of Cellular Reductants: Relevance to understanding the beneficial therapeutic effects of SOD mimics in vivo

Abstract

Historically cationic Mn(III) N-alkylpyridylporphyrins(MnTalkyl-2(or 3)PyP5+) have been regarded as the most powerful SOD mimics/antioxidants. During dismutation process they reduce and oxidize O2.- with identical rate constants, equally well accepting and donating electrons. They further readily oxidize ascorbate and glutathione and reduce oxygen. Given the abundance of O2 and cellular reductants, MnPs may act in vivo as pro-oxidants - catalysts of ascorbate-driven O2 reduction to O2. /H2O2. To support such “opposing” line of thoughts we explored a very simple and straightforward superoxide-specific SOD-deficient E. coli system, where cationic MnPs act as powerful SOD mimics. Yet, if ascorbate is added to the medium SOD mimics become oxidants, causing oxidative damage to both wild and SOD-deficient strains and disabling their growth. Ascorbate itself imposes no damage. We have previously observed that MnTE-2-PyP5+ alone suppresses oxidative stress in a 4T1 breast cancer mouse model. Yet, if co-administered with ascorbate, its equally potent analogue MnTnHex-2-PyP5+ increases tumor oxidative burden in the same model. Further, MnP/ascorbate system acts as pro-oxidant in five cancer cell lines. Importantly, upon reduction with ascorbate, cationic MnPs lose single charge on metal site which increases their lipophilicity up to 3 orders of magnitude and in turn their bioavailibility. Emerging experimental evidence, thus, suggests that indeed the beneficial effects of Mn porphyrin-based SOD mimics may be exerted via pro-oxidative action also. Upon increased MnP- catalyzed production of peroxide either with exogenous or endogenous ascorbate, cell would react with adaptive response by upregulation of endogenous antioxidative defenses ; final outcome may appear as anti-oxidative action of MnPs. E. coli system, also, reacts via adaptive response and recover time-dependently after initial oxidative attack. The type of action (anti- or pro-oxidative) will depend upon the cellular levels of reactive species, endogenous antioxidants and ratio of SOD and peroxide-removing systems. Such data ask for further exploration of the nature of the therapeutic effects of synthetic SOD mimics in vivo.