Journal article
Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate
Antioxidants, Vol.10(4), p.614
04/16/2021
DOI: 10.3390/antiox10040614
PMCID: PMC8073689
PMID: 33923601
Abstract
Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH
), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide (H
O
), resulting in the killing of PDACs but not normal cells. Recent studies have demonstrated that P-AscH
radio-sensitizes PDAC but is a radioprotector to normal cells and tissues. Several mechanisms have been hypothesized to explain the dual roles of P-AscH
in radiation-induced toxicity including the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), RelB, as well as changes in bioenergetic profiles. We have found that P-AscH
in conjunction with radiation increases Nrf2 in both cancer cells and normal cells. Although P-AscH
with radiation decreases RelB in cancer cells vs. normal cells, the knockout of RelB does not radio-sensitize PDACs. Cellular bioenergetic profiles demonstrate that P-AscH
with radiation increases the ATP demand/production rate (glycolytic and oxidative phosphorylation) in both PDACs and normal cells. Knocking out catalase results in P-AscH
radio-sensitization in PDACs. In a phase I trial where P-AscH
was included as an adjuvant to the standard of care, short-term survivors had higher catalase levels in tumor tissue, compared to long-term survivors. These data suggest that P-AscH
radio-sensitizes PDACs through increased peroxide flux. Catalase levels could be a possible indicator for how tumors will respond to P-AscH
.
Details
- Title: Subtitle
- Catalase Modulates the Radio-Sensitization of Pancreatic Cancer Cells by Pharmacological Ascorbate
- Creators
- Juan Du - University of IowaRory S Carroll - University of IowaGarett J Steers - University of IowaBrett A Wagner - University of IowaBrianne R O'Leary - University of IowaChris S Jensen - University of IowaGarry R Buettner - University of IowaJoseph J Cullen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Antioxidants, Vol.10(4), p.614
- DOI
- 10.3390/antiox10040614
- PMID
- 33923601
- PMCID
- PMC8073689
- NLM abbreviation
- Antioxidants (Basel)
- ISSN
- 2076-3921
- eISSN
- 2076-3921
- Grant note
- T32 CA148062-01 / NIH HHS NA / Gateway for Cancer Research P01 CA217797 / NIH HHS
- Language
- English
- Date published
- 04/16/2021
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984186661502771
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