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.
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Authors | Ines Batinic-Haberle, Artak Tovmasyan, Ivan Spasojevic |
Journal | Antioxidants & redox signaling
(Antioxid Redox Signal)
Vol. 29
Issue 16
Pg. 1691-1724
(12 01 2018)
ISSN: 1557-7716 [Electronic] United States |
PMID | 29926755
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
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Chemical References |
- Antineoplastic Agents
- Metal-Organic Frameworks
- Porphyrins
- Protective Agents
- Manganese
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Topics |
- Animals
- Antineoplastic Agents
(chemistry, metabolism, pharmacology)
- Humans
- Manganese
(chemistry, metabolism, pharmacology)
- Metal-Organic Frameworks
(chemistry, metabolism, pharmacology)
- Neoplasms
(drug therapy, pathology)
- Oxidation-Reduction
- Oxidative Stress
(drug effects)
- Porphyrins
(chemistry, metabolism, pharmacology)
- Protective Agents
(chemistry, metabolism, pharmacology)
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