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

Xiaodong Ye, Diane Fels, Artak Tovmasyan, Katherine M. Aird, Casey Dedeugd, Jennifer L. Allensworth, Ivan Kos, Won Park, Ivan Spasojevic, Gayathri R. Devi, Mark W. Dewhirst, Kam W. Leong, Ines Batinic-Haberle

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Abstract

Due to the ability to easily accept and donate electrons Mn(III)N-alkylpyridylporphyrins (MnPs) can dismute O 2 ·-, reduce peroxynitrite, but also generate reactive species and behave as pro-oxidants if conditions favour such action. Herein two ortho isomers, MnTE-2-PyP 5+, MnTnHex-2-PyP 5+, and a meta isomer MnTnHex-3-PyP 5+, 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-PyP 5+ was the most efficacious catalyst for peroxide production, while MnTnHex-3-PyP 5+ is most prone to oxidative degradation with H 2 , 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.

Original languageEnglish (US)
Pages (from-to)1289-1306
Number of pages18
JournalFree Radical Research
Volume45
Issue number11-12
DOIs
StatePublished - Nov 1 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry

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    Ye, X., Fels, D., Tovmasyan, A., Aird, K. M., Dedeugd, C., Allensworth, J. L., Kos, I., Park, W., Spasojevic, I., Devi, G. R., Dewhirst, M. W., Leong, K. W., & Batinic-Haberle, I. (2011). Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate. Free Radical Research, 45(11-12), 1289-1306. https://doi.org/10.3109/10715762.2011.616199