Journal article
Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Molecular cancer research, Vol.17(10), pp.2102-2114
10/01/2019
DOI: 10.1158/1541-7786.MCR-19-0381
PMCID: PMC6774825
PMID: 31337671
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.
Details
- Title: Subtitle
- Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
- Creators
- Visarut Buranasudja - University of IowaClaire M. Doskey - University of IowaAdrienne R. Gibson - University of IowaBrett A. Wagner - University of IowaJuan Du - University of IowaDavid J. Gordon - University of IowaStacia L. Koppenhafer - University of IowaJoseph J. Cullen - University of IowaGarry R. Buettner - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.17(10), pp.2102-2114
- DOI
- 10.1158/1541-7786.MCR-19-0381
- PMID
- 31337671
- PMCID
- PMC6774825
- NLM abbreviation
- Mol Cancer Res
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- P42ES013661 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) R37CA217910 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30 CA086862 / Holden Comprehensive Cancer Center, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 CA169046; R01 GM073929; R01 CA184051; P01 CA217797; R37 CA217910; T32 CA078586; P42 ES013661 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30 CA086862 / Carver College of Medicine, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/01/2019
- Academic Unit
- Stead Family Department of Pediatrics; Surgery; Hematology/Oncology; Radiation Oncology; Iowa Superfund Research Program
- Record Identifier
- 9984285538102771
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