Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities

Ines Batinic-Haberle, Ivan Spasojevic, Hubert M. Tse, Artak Tovmasyan, Zrinka Rajic, Daret K.St Clair, Zeljko Vujaskovic, Mark W. Dewhirst, Jon D. Piganelli

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Themost efficaciousMn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and electrostatic facilitation for the reaction with negatively charged species such as O2•- and ONOO-. Those are Mn(III) meso tetrakis(N-alkylpyridinium-2-yl)porphyrins, more specificallyMnTE- 2-PyP5+ (AEOL10113) and MnTnHex-2-PyP5+ (where alkyls are ethyl and n-hexyl, respectively), and their imidazolium analog, MnTDE-2-ImP 5+ (AEOL10150, Mn(III) meso tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin). The efficacy of MnPs in vivo is determined not only by the compound antioxidant potency, but also by its bioavailability. The former is greatly affected by the lipophilicity, size, structure, and overall shape of the compound. These porphyrins have the ability to both eliminate reactive oxygen species and impact the progression of oxidative stressdependent signaling events. This will effectively lead to the regulation of redox-dependent transcription factors and the suppression of secondary inflammatory- and oxidative stressmediated immune responses. We have reported on the inhibition of major transcription factors HIF-1α, AP-1, SP-1, and NF-ΚB by Mn porphyrins. While the prevailing mechanistic view of the suppression of transcription factors activation is via antioxidative action (presumably in cytosol), the prooxidative action ofMnPs in suppressing NF-ΚB activation in nucleus has been substantiated. Themagnitude of the effect is dependent upon the electrostatic (porphyrin charges) and thermodynamic factors (porphyrin redox ability). The prooxidative action of MnPs has been suggested to contribute at least in part to the in vitro anticancer action ofMnTE-2-PyP5+ in the presence of ascorbate, and in vivo when combined with chemotherapy of lymphoma. Given the remarkable therapeutic potential of metalloporphyrins, future studies are warranted to further our understanding of in vivo action/s of Mn porphyrins, particularly with respect to their subcellular distribution.

Original languageEnglish
Pages (from-to)95-113
Number of pages19
JournalAmino Acids
Volume42
Issue number1
DOIs
StatePublished - Jan 2012

Bibliographical note

Funding Information:
In writing this review, we acknowledge the financial help from the National Institutes for Allergy and Infectious Diseases [U19AI067798]; Duke University’s CTSA grant 1 UL 1 RR024128-01 from NCRR/NIH and NIH R01 DA024074; IS thanks NIH/NCI Duke Comprehensive Cancer Center Core Grant [5-P30-CA14236-29], and ZV to RO1 CA 098452. DKStC is grateful to CA 139843 and CA 07359. HMT is thankful to Cochrane-Weber Research Award and Research Advisory Council Award (Children’s Hospital of Pittsburgh and the University of Pittsburgh), MWD to CA40355-25, and JDS to Juvenile Diabetes Association #1-2005-80, American Diabetes Association CDA 7-07 CD-16. The authors appreciate helpful discussions with Gerardo Ferrer-Sueta.

Keywords

  • Cellular transcriptional activity
  • Mn porphyrins
  • NF-ΚB
  • Peroxynitrite scavengers
  • SOD mimics

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Clinical Biochemistry

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