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Antioxid Redox Signal. 2018 Dec 1;29(16):1691-1724. doi: 10.1089/ars.2017.7453. Epub 2018 Aug 28.

Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

Author information

1
1 Department of Radiation Oncology, Duke University School of Medicine , Durham, North Carolina.
2
2 Department of Medicine, Duke University School of Medicine , Durham, North Carolina.
3
3 PK/PD Core Laboratory, Pharmaceutical Research Shared Resource, Duke Cancer Institute , Durham, North Carolina.

Abstract

SIGNIFICANCE:

After approximatelty three decades of research, two Mn(III) porphyrins (MnPs), MnTE-2-PyP5+ (BMX-010, AEOL10113) and MnTnBuOE-2-PyP5+ (BMX-001), have progressed to five clinical trials. In parallel, another similarly potent metal-based superoxide dismutase (SOD) mimic-Mn(II)pentaaza macrocycle, GC4419-has been tested in clinical trial on application, identical to that of MnTnBuOE-2-PyP5+-radioprotection of normal tissue in head and neck cancer patients. This clearly indicates that Mn complexes that target cellular redox environment have reached sufficient maturity for clinical applications. Recent Advances: While originally developed as SOD mimics, MnPs undergo intricate interactions with numerous redox-sensitive pathways, such as those involving nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (Nrf2), thereby impacting cellular transcriptional activity. An increasing amount of data support the notion that MnP/H2O2/glutathione (GSH)-driven catalysis of S-glutathionylation of protein cysteine, associated with modification of protein function, is a major action of MnPs on molecular level.

CRITICAL ISSUES:

Differential effects of MnPs on normal versus tumor cells/tissues, which support their translation into clinic, arise from differences in their accumulation and redox environment of such tissues. This in turn results in different yields of MnP-driven modifications of proteins. Thus far, direct evidence for such modification of NF-κB, mitogen-activated protein kinases (MAPK), phosphatases, Nrf2, and endogenous antioxidative defenses was provided in tumor, while indirect evidence shows the modification of NF-κB and Nrf2 translational activities by MnPs in normal tissue.

FUTURE DIRECTIONS:

Studies that simultaneously explore differential effects in same animal are lacking, while they are essential for understanding of extremely intricate interactions of metal-based drugs with complex cellular networks of normal and cancer cells/tissues.

KEYWORDS:

BMX-001; M40403/GC4403; Mn porphyrins; SOD mimics; cancer; protein cysteine oxidation; radioprotection

PMID:
29926755
PMCID:
PMC6207162
[Available on 2019-12-01]
DOI:
10.1089/ars.2017.7453

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