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, E1/2 (MnIIIP/MnIIP) and lipophilicity, were explored. Employing MnIIIP/MnIIP 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.

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

“…Consequently, a maximal production of H 2 O 2 and other reactive species can be achieved, causing a more efficient tumor destruction. Promising results of such combinational catalytic therapy have been reported (48,95,130). In vitro experiments have shown that some cancer cell lines are more sensitive to either cationic MnPs or Fe porphyrins (FePs) alone and to the MnP-ascorbate combination than are normal cells (121).…”

“…The E. coli-based discovery of MnP-ascorbate cytotoxicity (92) brought up the idea that the combination can be used for anticancer treatment (48,95,117,130). The therapeutic potential of pharmacological doses of ascorbate alone has already been demonstrated in several preclinical and clinical trials (46,61,83,127) and is based on the increased production of reactive species due to ascorbate oxidation, catalyzed by endogenous metalloproteins (36).…”

“…For example, increased production of ROS explains the toxicity of some MnPs when they are combined with natural reductants. Such MnPs can be easily reduced by ascorbate, tetrahydrobiopterin, or glutathione (18,21,130) (Fig. 11A) (15).…”

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…Due to the biocompatible E 1/2 and favorable electrostatics (26,28,177), the pentacationic electrophilic Mn(III) N-substituted pyridylporphyrins rapidly react with anionic deprotonated forms of cellular reductants: ascorbate, glutathione, cysteine, and protein thiols (29,33,299). In such reactions, the MnPs act as oxidants.…”

“…When administered along with MnP, the metal complex would catalyze glutathionylation of p65 subunit of NF-jB by H 2 O 2 and GSH. Use of the redox-active metal complex along with the source of H 2 O 2 has been proposed by us and others (268,299) as a prospective anticancer treatment.…”