Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.
Published
Journal Article (Review)
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.
Full Text
Duke Authors
Cited Authors
- Batinic-Haberle, I; Tovmasyan, A; Spasojevic, I
Published Date
- December 1, 2018
Published In
Volume / Issue
- 29 / 16
Start / End Page
- 1691 - 1724
PubMed ID
- 29926755
Pubmed Central ID
- 29926755
Electronic International Standard Serial Number (EISSN)
- 1557-7716
Digital Object Identifier (DOI)
- 10.1089/ars.2017.7453
Language
- eng
Conference Location
- United States