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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Humans
  • Manganese / chemistry
  • Manganese / metabolism
  • Manganese / pharmacology*
  • Metal-Organic Frameworks / chemistry
  • Metal-Organic Frameworks / metabolism
  • Metal-Organic Frameworks / pharmacology*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*
  • Porphyrins / chemistry
  • Porphyrins / metabolism
  • Porphyrins / pharmacology*
  • Protective Agents / chemistry
  • Protective Agents / metabolism
  • Protective Agents / pharmacology*


  • Antineoplastic Agents
  • Metal-Organic Frameworks
  • Porphyrins
  • Protective Agents
  • Manganese