Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models

Joshua D Schoenfeld; Zita A Sibenaller; Kranti A Mapuskar; Megan D Bradley; Brett A Wagner; Garry R Buettner; Varun Monga; Mohammed Milhem; Douglas R Spitz; Bryan G Allen

doi:10.1016/j.redox.2017.09.012

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Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models

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Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models

Joshua D Schoenfeld, Zita A Sibenaller, Kranti A Mapuskar, Megan D Bradley, Brett A Wagner, Garry R Buettner, Varun Monga, Mohammed Milhem, Douglas R Spitz and Bryan G Allen

Redox biology, Vol.14, pp.417-422

04/2018

DOI: 10.1016/j.redox.2017.09.012

PMCID: PMC5651553

PMID: 29069637

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Abstract

Soft tissue sarcomas are a histologically heterogeneous group of rare mesenchymal cancers for which treatment options leading to increased overall survival have not improved in over two decades. The current study shows that pharmacological ascorbate (systemic high dose vitamin C achieving ≥ 20mM plasma levels) is a potentially efficacious and easily integrable addition to current standard of care treatment strategies in preclinical models of fibrosarcoma and liposarcoma both in vitro and in vivo. Furthermore, enhanced ascorbate-mediated toxicity and DNA damage in these sarcoma models were found to be dependent upon H2O2 and intracellular labile iron. Together, these data support the hypothesis that pharmacological ascorbate may represent an easily implementable and non-toxic addition to conventional sarcoma therapies based on taking advantage of fundamental differences in cancer cell oxidative metabolism. •Ascorbate sensitizes sarcoma cells to radiation- or chemo-therapy by a mechanism involving redox active metal ions and H2O2.•Pharmacological ascorbate in combination with radio-chemo-therapy decreases sarcoma disease burden in murine xenografts.•Ascorbate-mediated DNA damage is dependent on intracellular redox active iron.

Chemotherapy sensitization

Sarcoma

Radiation sensitization

Labile iron

Pharmacological ascorbate

Details

Title: Subtitle: Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models
Creators: Joshua D Schoenfeld - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Zita A Sibenaller - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Kranti A Mapuskar - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Megan D Bradley - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Brett A Wagner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Garry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Varun Monga - Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Mohammed Milhem - Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Bryan G Allen - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, United States
Resource Type: Journal article
Publication Details: Redox biology, Vol.14, pp.417-422
DOI: 10.1016/j.redox.2017.09.012
PMID: 29069637
PMCID: PMC5651553
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier B.V
Grant note: name: CCSG, award: P30-CA086862; DOI: 10.13039/100008893, name: University of Iowa, award: R01-CA182804, R01-CA169046, T32-GM007337, T32-CA078586
Language: English
Date published: 04/2018
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Radiation Oncology; Internal Medicine
Record Identifier: 9984047626402771

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