Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels

Brianne R. O’Leary; Amanda L. Kalen; Amanda N. Pope; Prabhat C. Goswami; Joseph J. Cullen

doi:10.1667/RADE-22-00182.1

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Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels

Journal article

Peer reviewed

Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels

Brianne R. O’Leary, Amanda L. Kalen, Amanda N. Pope, Prabhat C. Goswami and Joseph J. Cullen

Radiation research, Vol.200(5), pp.444-455

11/2023

DOI: 10.1667/RADE-22-00182.1

PMCID: PMC10699322

PMID: 37758045

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10699322/pdf/nihms-1945429.pdfView

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Abstract

Pharmacological ascorbate (P-AscH–, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH– induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway. Both non-tumorigenic pancreatic ductal epithelial and PDAC cells display decreased clonogenic survival and increased doubling times after radiation treatment. In contrast, the addition of P-AscH– to radiation increases clonogenic survival and decreases the doubling time of non-tumorigenic epithelial cells but decreasing clonogenic survival and increasing the doubling time of PDAC cells. Results from the mitotic index and propidium iodide assays showed that while the P-AscH– treatments did not affect radiation-induced G2-checkpoint activation, it enhanced G2-accumulation. The addition of catalase reverses the increases in G2-accumulation, indicating a peroxide-mediated mechanism. In addition, P-AscH– treatment of PDAC cells suppresses radiation-induced accumulation of cyclin B1 protein levels. Both translational and post-translational pathways appear to regulate cyclin B1 protein levels after the combination treatment of PDAC cells with P-AscH– and radiation. The protein changes seen are reversed by the addition of catalase suggesting that hydrogen peroxide mediates P-AscH– induced radiation sensitization of PDAC cells by enhancing G2-accumulation and reducing cyclin B1 protein levels.

Details

Title: Subtitle: Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels
Creators: Brianne R. O’Leary - University of Iowa
Amanda L. Kalen - University of Iowa
Amanda N. Pope - University of Iowa
Prabhat C. Goswami - University of Iowa
Joseph J. Cullen - University of Iowa
Resource Type: Journal article
Publication Details: Radiation research, Vol.200(5), pp.444-455
DOI: 10.1667/RADE-22-00182.1
PMID: 37758045
PMCID: PMC10699322
NLM abbreviation: Radiat Res
ISSN: 0033-7587
eISSN: 1938-5404
Language: English
Electronic publication date: 09/27/2023
Date published: 11/2023
Academic Unit: Surgery; Radiation Oncology
Record Identifier: 9984473774002771

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