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Antioxid Redox Signal. 2018 Nov 1;29(13):1196-1214. doi: 10.1089/ars.2017.7218. Epub 2018 Mar 27.

Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate.

Author information

1
1 Department of Radiation Oncology, Duke University School of Medicine , Durham, North Carolina.
2
2 Department of Pathology, University of Arizona , Tucson, Arizona.
3
3 Departamento de Quimica, CCEN , Universidade Federal da Paraiba, Joao Pessoa, Brazil .
4
4 Canadian Economic Analysis Department , Bank of Canada, Ottawa, Canada .
5
5 Department of Biochemistry, Faculty of Medicine, Kuwait University , Kuwait, Kuwait .
6
6 Palo Alto Veterans Institute for Research , Palo Alto, California.
7
7 Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California.
8
8 Geriatric Research. Education, and Clinical Center (GRECC) , VA Palo Alto Health Care System, Palo Alto, California.
9
9 Department of Pharmacology, University of Arizona , Tucson, Arizona.
10
10 Department of Medicine, Duke University School of Medicine , Durham, North Carolina.
11
11 PK/PD Core Laboratory, Pharmaceutical Research Shared Resource, Duke Cancer Institute , Durham, North Carolina.

Abstract

AIMS:

We aim here to demonstrate that radiation (RT) enhances tumor sensitization by only those Mn complexes that are redox active and cycle with ascorbate (Asc), thereby producing H2O2 and utilizing it subsequently in protein S-glutathionylation in a glutathione peroxidase (GPx)-like manner. In turn, such compounds affect cellular redox environment, described by glutathione disulfide (GSSG)/glutathione (GSH) ratio, and tumor growth. To achieve our goal, we tested several Mn complexes of different chemical and physical properties in cellular and animal flank models of 4T1 breast cancer cell. Four other cancer cell lines were used to substantiate key findings.

RESULTS:

Joint administration of cationic Mn porphyrin (MnP)-based redox active compounds, MnTE-2-PyP5+ or MnTnBuOE-2-PyP5+ with RT and Asc contributes to high H2O2 production in cancer cells and tumor, which along with high MnP accumulation in cancer cells and tumor induces the largest suppression of cell viability and tumor growth, while increasing GSSG/GSH ratio and levels of total S-glutathionylated proteins. Redox-inert MnP, MnTBAP3- and two other different types of redox-active Mn complexes (EUK-8 and M40403) were neither efficacious in the cellular nor in the animal model. Such outcome is in accordance with their inability to catalyze Asc oxidation and mimic GPx.

INNOVATION:

We provided here the first evidence how structure-activity relationship between the catalytic potency and the redox properties of Mn complexes controls their ability to impact cellular redox environment and thus enhance the radiation and ascorbate-mediated tumor suppression.

CONCLUSIONS:

The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects.

KEYWORDS:

EUK-8; M40403; MnTE-2-PyP5+; MnTnBuOE-2-PyP5+; SOD mimics; ascorbate; radiosensitization

PMID:
29390861
PMCID:
PMC6157436
[Available on 2019-11-01]
DOI:
10.1089/ars.2017.7218

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