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Metabolism

Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage

Visarut Buranasudja, Claire M. Doskey, Adrienne R. Gibson, Brett A. Wagner, Juan Du, David J. Gordon, Stacia L. Koppenhafer, Joseph J. Cullen and Garry R. Buettner
Visarut Buranasudja
Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa.
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  • ORCID record for Visarut Buranasudja
Claire M. Doskey
Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa.
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Adrienne R. Gibson
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa.
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Brett A. Wagner
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa.
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  • ORCID record for Brett A. Wagner
Juan Du
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa.Department of Surgery, The University of Iowa, Iowa City, Iowa.
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David J. Gordon
Department of Pediatrics, The University of Iowa, Iowa City, Iowa.
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Stacia L. Koppenhafer
Department of Pediatrics, The University of Iowa, Iowa City, Iowa.
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Joseph J. Cullen
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa.Department of Surgery, The University of Iowa, Iowa City, Iowa.Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa.
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Garry R. Buettner
Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa.Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa.
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  • For correspondence: garry-buettner@uiowa.edu
DOI: 10.1158/1541-7786.MCR-19-0381 Published October 2019
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Abstract

The clinical potential of pharmacologic ascorbate (P-AscH−; intravenous delivery achieving mmol/L concentrations in blood) as an adjuvant in cancer therapy is being reevaluated. At mmol/L concentrations, P-AscH− is thought to exhibit anticancer activity via generation of a flux of H2O2 in tumors, which leads to oxidative distress. Here, we use cell culture models of pancreatic cancer to examine the effects of P-AscH− on DNA damage, and downstream consequences, including changes in bioenergetics. We have found that the high flux of H2O2 produced by P-AscH− induces DNA damage. In response to this DNA damage, we observed that PARP1 is hyperactivated. Using our unique absolute quantitation, we found that P-AscH− mediated the overactivation of PARP1, which results in consumption of NAD+, and subsequently depletion of ATP leading to mitotic cell death. We have also found that Chk1 plays a major role in the maintenance of genomic integrity following treatment with P-AscH−. Hyperactivation of PARP1 and DNA repair are ATP-consuming processes. Using a Seahorse XF96 analyzer, we demonstrated that the severe decrease in ATP after challenging with P-AscH− is because of increased demand, not changes in the rate of production. Genetic deletion and pharmacologic inhibition of PARP1 preserved both NAD+ and ATP; however, the toxicity of P-AscH− remained. These data indicate that disruption of bioenergetics is a secondary factor in the toxicity of P-AscH−; damage to DNA appears to be the primary factor.

Implications: Efforts to leverage P-AscH− in cancer therapy should first focus on DNA damage.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:2102–14

  • Received April 10, 2019.
  • Revision received June 21, 2019.
  • Accepted July 17, 2019.
  • Published first July 23, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (10)
October 2019
Volume 17, Issue 10
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Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Visarut Buranasudja, Claire M. Doskey, Adrienne R. Gibson, Brett A. Wagner, Juan Du, David J. Gordon, Stacia L. Koppenhafer, Joseph J. Cullen and Garry R. Buettner
Mol Cancer Res October 1 2019 (17) (10) 2102-2114; DOI: 10.1158/1541-7786.MCR-19-0381

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Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Visarut Buranasudja, Claire M. Doskey, Adrienne R. Gibson, Brett A. Wagner, Juan Du, David J. Gordon, Stacia L. Koppenhafer, Joseph J. Cullen and Garry R. Buettner
Mol Cancer Res October 1 2019 (17) (10) 2102-2114; DOI: 10.1158/1541-7786.MCR-19-0381
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Molecular Cancer Research
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