Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate

Abstract

Due to the ability to easily accept and donate electrons Mn(III)N-alkylpyridylporphyrins (MnPs) can dismute O₂ ^·−, reduce peroxynitrite, but also generate reactive species and behave as pro-oxidants if conditions favour such action. Herein two ortho isomers, MnTE-2-PyP⁵⁺, MnTnHex-2-PyP⁵⁺, and a meta isomer MnTnHex-3-PyP⁵⁺, which differ greatly with regard to their metal-centered reduction potential, E_1/2 (Mn^IIIP/Mn^IIP) and lipophilicity, were explored. Employing Mn^IIIP/Mn^IIP redox system for coupling with ascorbate, these MnPs catalyze ascorbate oxidation and thus peroxide production. Consequently, cancer oxidative burden may be enhanced, which in turn would suppress its growth. Cytotoxic effects on Caco-2, Hela, 4T1, HCT116 and SUM149 were studied. When combined with ascorbate, MnPs killed cancer cells via peroxide produced outside of the cell. MnTE-2-PyP⁵⁺ was the most efficacious catalyst for peroxide production, while MnTnHex-3-PyP⁵⁺ is most prone to oxidative degradation with H₂ , and thus the least efficacious. A 4T1 breast cancer mouse study of limited scope and success was conducted. The tumour oxidative stress was enhanced and its microvessel density reduced when mice were treated either with ascorbate or MnP/ascorbate; the trend towards tumour growth suppression was detected.

Keywords::

• Mn porphyrin
• cancer cells
• ascorbate
• SOD mimics
• oxidative stress
• MnTE-2-PyP⁵⁺

This paper was first published online on Early online on 14 October 2011.