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Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.

Publication ,  Journal Article
Evans, MK; Tovmasyan, A; Batinic-Haberle, I; Devi, GR
Published in: Free Radic Biol Med
March 2014

Resistance to therapy-mediated apoptosis in inflammatory breast cancer, an aggressive and distinct subtype of breast cancer, was recently attributed to increased superoxide dismutase (SOD) expression, glutathione (GSH) content, and decreased accumulation of reactive species. In this study, we demonstrate the unique ability of two Mn(III) N-substituted pyridylporphyrin (MnP)-based SOD mimics (MnTE-2-PyP(5+) and MnTnBuOE-2-PyP(5+)) to catalyze oxidation of ascorbate, leading to the production of excessive levels of peroxide, and in turn cell death. The accumulation of peroxide, as a consequence of MnP+ascorbate treatment, was fully reversed by the administration of exogenous catalase, showing that hydrogen peroxide is essential for cell death. Cell death as a consequence of the action of MnP+ascorbate corresponded to decreases in GSH levels, prosurvival signaling (p-NF-κB, p-ERK1/2), and in expression of X-linked inhibitor of apoptosis protein, the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and annexin V staining, administration of a pan-caspase inhibitor, Q-VD-OPh, did not reverse the observed cytotoxicity. MnP+ascorbate-treated cells showed nuclear translocation of apoptosis-inducing factor, suggesting the possibility of a mechanism of caspase-independent cell death. Pharmacological ascorbate has already shown promise in recently completed phase I clinical trials, in which its oxidation and subsequent peroxide formation was catalyzed by endogenous metalloproteins. The catalysis of ascorbate oxidation by an optimized metal-based catalyst (such as MnP) carries a large therapeutic potential as an anticancer agent by itself or in combination with other modalities such as radio- and chemotherapy.

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Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

March 2014

Volume

68

Start / End Page

302 / 314

Location

United States

Related Subject Headings

  • Superoxide Dismutase
  • Reactive Oxygen Species
  • Peroxides
  • Oxidation-Reduction
  • NF-kappa B
  • Metalloporphyrins
  • Hydrogen Peroxide
  • Humans
  • Female
  • Caspases
 

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Evans, M. K., Tovmasyan, A., Batinic-Haberle, I., & Devi, G. R. (2014). Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death. Free Radic Biol Med, 68, 302–314. https://doi.org/10.1016/j.freeradbiomed.2013.11.031
Evans, Myron K., Artak Tovmasyan, Ines Batinic-Haberle, and Gayathri R. Devi. “Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.Free Radic Biol Med 68 (March 2014): 302–14. https://doi.org/10.1016/j.freeradbiomed.2013.11.031.
Evans MK, Tovmasyan A, Batinic-Haberle I, Devi GR. Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death. Free Radic Biol Med. 2014 Mar;68:302–14.
Evans, Myron K., et al. “Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.Free Radic Biol Med, vol. 68, Mar. 2014, pp. 302–14. Pubmed, doi:10.1016/j.freeradbiomed.2013.11.031.
Evans MK, Tovmasyan A, Batinic-Haberle I, Devi GR. Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death. Free Radic Biol Med. 2014 Mar;68:302–314.
Journal cover image

Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

March 2014

Volume

68

Start / End Page

302 / 314

Location

United States

Related Subject Headings

  • Superoxide Dismutase
  • Reactive Oxygen Species
  • Peroxides
  • Oxidation-Reduction
  • NF-kappa B
  • Metalloporphyrins
  • Hydrogen Peroxide
  • Humans
  • Female
  • Caspases