Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

Artak Tovmasyan, Jacqueline C. Bueno-Janice, Melba C. Jaramillo, Romulo S. Sampaio, Julio S. Reboucas, Natalia Kyui, Ludmil Benov, Brian Deng, Ting Ting Huang, Margaret E Tome, Ivan Spasojevic, Ines Batinic-Haberle

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Aims: We aim here to demonstrate that radiation (RT) enhances tumor sensitization by only those Mn complexes that are redox active and cycle with ascorbate (Asc), thereby producing H2O2 and utilizing it subsequently in protein S-glutathionylation in a glutathione peroxidase (GPx)-like manner. In turn, such compounds affect cellular redox environment, described by glutathione disulfide (GSSG)/glutathione (GSH) ratio, and tumor growth. To achieve our goal, we tested several Mn complexes of different chemical and physical properties in cellular and animal flank models of 4T1 breast cancer cell. Four other cancer cell lines were used to substantiate key findings. Results: Joint administration of cationic Mn porphyrin (MnP)-based redox active compounds, MnTE-2-PyP5+ or MnTnBuOE-2-PyP5+ with RT and Asc contributes to high H2O2 production in cancer cells and tumor, which along with high MnP accumulation in cancer cells and tumor induces the largest suppression of cell viability and tumor growth, while increasing GSSG/GSH ratio and levels of total S-glutathionylated proteins. Redox-inert MnP, MnTBAP3- and two other different types of redox-active Mn complexes (EUK-8 and M40403) were neither efficacious in the cellular nor in the animal model. Such outcome is in accordance with their inability to catalyze Asc oxidation and mimic GPx. Innovation: We provided here the first evidence how structure-activity relationship between the catalytic potency and the redox properties of Mn complexes controls their ability to impact cellular redox environment and thus enhance the radiation and ascorbate-mediated tumor suppression. Conclusions: The interplay between the accumulation of cationic MnPs and their potency as catalysts for oxidation of Asc, protein cysteines, and GSH controls the magnitude of their anticancer therapeutic effects.

Original languageEnglish (US)
Pages (from-to)1196-1214
Number of pages19
JournalAntioxidants and Redox Signaling
Volume29
Issue number13
DOIs
StatePublished - Nov 1 2018

Fingerprint

Oxidation-Reduction
Tumors
Glutathione Disulfide
Radiation
Cells
Growth
Porphyrins
Neoplasms
Glutathione
Protein S
Glutathione Peroxidase
Animals
Oxidation
Animal Models
Chemical properties
Cysteine
Therapeutic Uses
Structure-Activity Relationship
Physical properties
Innovation

Keywords

  • ascorbate
  • EUK-8
  • M40403
  • MnTE-2-PyP
  • MnTnBuOE-2-PyP
  • radiosensitization
  • SOD mimics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Tovmasyan, A., Bueno-Janice, J. C., Jaramillo, M. C., Sampaio, R. S., Reboucas, J. S., Kyui, N., ... Batinic-Haberle, I. (2018). Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate. Antioxidants and Redox Signaling, 29(13), 1196-1214. https://doi.org/10.1089/ars.2017.7218

Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate. / Tovmasyan, Artak; Bueno-Janice, Jacqueline C.; Jaramillo, Melba C.; Sampaio, Romulo S.; Reboucas, Julio S.; Kyui, Natalia; Benov, Ludmil; Deng, Brian; Huang, Ting Ting; Tome, Margaret E; Spasojevic, Ivan; Batinic-Haberle, Ines.

In: Antioxidants and Redox Signaling, Vol. 29, No. 13, 01.11.2018, p. 1196-1214.

Research output: Contribution to journalArticle

Tovmasyan, A, Bueno-Janice, JC, Jaramillo, MC, Sampaio, RS, Reboucas, JS, Kyui, N, Benov, L, Deng, B, Huang, TT, Tome, ME, Spasojevic, I & Batinic-Haberle, I 2018, 'Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate', Antioxidants and Redox Signaling, vol. 29, no. 13, pp. 1196-1214. https://doi.org/10.1089/ars.2017.7218
Tovmasyan, Artak ; Bueno-Janice, Jacqueline C. ; Jaramillo, Melba C. ; Sampaio, Romulo S. ; Reboucas, Julio S. ; Kyui, Natalia ; Benov, Ludmil ; Deng, Brian ; Huang, Ting Ting ; Tome, Margaret E ; Spasojevic, Ivan ; Batinic-Haberle, Ines. / Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate. In: Antioxidants and Redox Signaling. 2018 ; Vol. 29, No. 13. pp. 1196-1214.
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AU - Jaramillo, Melba C.

AU - Sampaio, Romulo S.

AU - Reboucas, Julio S.

AU - Kyui, Natalia

AU - Benov, Ludmil

AU - Deng, Brian

AU - Huang, Ting Ting

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