Comprehensive Study of GPx Activity of Different Classes of Redox-Active Therapeutics - Implications for Their Therapeutic Actions

Bueno-Janice, Jacqueline C.; Tovmasyan, Artak; Batinić‐Haberle, Ines

doi:10.1016/j.freeradbiomed.2015.10.227

Cited by 11 publications

(23 citation statements)

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“…We have already indicated that cationic ortho Mn(III) N -substituted pyridyl-porphyrins bear therapeutic potential as catalysts for ascorbate oxidation with concomitant production of cytotoxic H 2 O 2 [33, 45, 69]. H 2 O 2 can subsequently be employed by MnP to oxidize or S -glutathionylate critical protein thiols, thereby affecting cell survival pathways [8-11, 32, 70] ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…We undertook this study to identify those properties of MnP that affect its ability to cycle with ascorbate thereby producing H 2 O 2 and to correlate such ability with cytotoxicity to cells and tumors. Studies are also in progress to understand the impact of the chemical and physical properties of MnP on a subsequent step - MnP/H 2 O 2 /GSH-driven oxidation of protein thiols [32, 74]. …”

Section: Resultsmentioning

confidence: 99%

“…Like SOD enzyme, its mimic must be able to equally efficiently oxidize and reduce O 2 .− , thus operating at E 1/2 which is right in between the reduction and oxidation potential of O 2 .− 2 , in the range of ~ +200 to ~ +400 mV vs NHE [42]. It is important to note that SOD-like ability of MnPs parallels their ability to undergo all reactions thus far studied, such as reduction of ONOO − [68], catalase-like activity [54], ability to catalyze ascorbate oxidation (this work) and ability to mimic GPx enzyme [32]. …”

Section: Resultsmentioning

confidence: 99%

“…Differential levels of RS are at least in part due to the differential expression and/or activities of endogenous antioxidant defenses such as superoxide dismutases (SOD), glutathione peroxidases (GPx), catalase and peroxiredoxins [8, 9, 15-31]. Substantial evidence was provided that MnPs are involved in the production of H 2 O 2 ; moreover MnP uses H 2 O 2 along with GSH in the catalysis of S -glutathionylation of signaling proteins in either thiol-oxidase or GPx-like fashion [10, 11, 32, 33]. Subsequently, the activities of those signaling proteins get suppressed; the magnitude of the effect controls cell survival.…”

Section: Introductionmentioning

confidence: 99%

“…In a subsequent study, we have addressed the Aim (ii) , i.e. the ability of different redox-active drugs, including MnPs, to oxidize protein thiols in a GPx-like fashion [32]. …”

Section: Introductionmentioning

confidence: 99%

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Anticancer therapeutic potential of Mn porphyrin/ascorbate system

Tovmasyan

Sampaio

Boss

et al. 2015

Free Radical Biology and Medicine

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105

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Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of MnIIIP/MnIIP redox couple, ranged from −200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2 > 0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1 mM) and MnPs (1 or 5 μM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL100 cells. Bell-shape relationship, essentially identical to vo(Asc)ox vs E1/2, was also demonstrated between MnP/Asc-controlled cellular cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)ox vs E1/2 relationships and cellular cytotoxicity, MnTE-2-PyP5+ was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP5+ were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP5+ (0.2 mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP5+ or ascorbate alone. In addition to optimal vo(Asc)ox, the compound mu...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In a subsequent study, we have addressed the Aim (ii) , i.e. the ability of different redox-active drugs, including MnPs, to oxidize protein thiols in a GPx-like fashion [32]. …”

Section: Introductionmentioning

confidence: 99%

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