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Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death.

Publication ,  Conference
Evans, M; Tovmasyan, A; Batinic-Haberle, I; Devi, G
Published in: Cancer Research
April 15, 2013

Resistance to therapy-mediated apoptosis in inflammatory breast cancer (IBC), an aggressive and distinct subtype of breast cancer was recently attributed to increased antioxidant expression (superoxide dismutase [SOD]; reduced glutathione) and decreased accumulation of reactive oxygen species (ROS) resulting in redox adaptation and increased cell survival. Mn porphyrins (MnPs) are amongst the most potent synthetic mimics of the antioxidant, superoxide dismutase (SOD). In the present study, we demonstrate the unique ability of two Mn porphyrin (MnP)-based SOD mimics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+) to act as pro-oxidants when combined with ascorbate (vitamin C) and enhance ROS-mediated cell death. We identified that the ethyl species, MnTE-2-PyP5+, was less stable than its butoxyethyl analog, MnTnBuOE-2-PyP5+, resulting in greater potency in inducing cytotoxicity via radical-driven oxidative degradation in cellular models of IBC isolated from patient tumors and an isogenic derivative with acquired resistance to therapeutic apoptosis. The combination of MnP and ascorbate induced accumulation of mitochondrial superoxide and H2O2-derived radicals in both therapy-sensitive and therapy-resistant cell lines. High intracellular ROS resulted in decreases in both pro-survival signaling (pNF-κB, pERK1/2) and expression of X-linked inhibitor of apoptosis protein (XIAP), 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 (QVD-OPh) did not reverse the observed cytotoxicity. Nuclear translocation of apoptosis inducing factor (AIF) was observed, suggesting a caspase-independent cell death following mitochondrial outer membrane permeabilization after treatment with this combination. In conclusion, this study provides the molecular basis of a novel MnP-based anti-cancer strategy and suggests the feasibility of using MnPs to sensitize cancer cells to many chemotherapies and radiotherapy that are dependent on potent induction of the oxidative stress response.Citation Format: Myron Evans, Artak Tovmasyan, Ines Batinic-Haberle, Gayathri Devi. Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5552. doi:10.1158/1538-7445.AM2013-5552Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 15, 2013

Volume

73

Issue

8_Supplement

Start / End Page

5552 / 5552

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

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Evans, M., Tovmasyan, A., Batinic-Haberle, I., & Devi, G. (2013). Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. In Cancer Research (Vol. 73, pp. 5552–5552). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2013-5552
Evans, Myron, Artak Tovmasyan, Ines Batinic-Haberle, and Gayathri Devi. “Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death.” In Cancer Research, 73:5552–5552. American Association for Cancer Research (AACR), 2013. https://doi.org/10.1158/1538-7445.am2013-5552.
Evans M, Tovmasyan A, Batinic-Haberle I, Devi G. Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. In: Cancer Research. American Association for Cancer Research (AACR); 2013. p. 5552–5552.
Evans, Myron, et al. “Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death.Cancer Research, vol. 73, no. 8_Supplement, American Association for Cancer Research (AACR), 2013, pp. 5552–5552. Crossref, doi:10.1158/1538-7445.am2013-5552.
Evans M, Tovmasyan A, Batinic-Haberle I, Devi G. Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. Cancer Research. American Association for Cancer Research (AACR); 2013. p. 5552–5552.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 15, 2013

Volume

73

Issue

8_Supplement

Start / End Page

5552 / 5552

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis