Journal article
Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer
Radiation research, Vol.191(1), pp.43-51
01/2019
DOI: 10.1667/RR15189.1
PMCID: PMC6441967
PMID: 30376411
Abstract
Pharmacologic ascorbate (P-AscH
) is emerging as a promising adjuvant for advanced pancreatic cancer. P-AscH
generates hydrogen peroxide (H
O
), leading to selective cancer cell cytotoxicity. Catalytic manganoporphyrins, such as MnT4MPyP, can increase the rate of oxidation of P-AscH
, thereby increasing the flux of H
O
, resulting in increased cytotoxicity. We hypothesized that a multimodal treatment approach, utilizing a combination of P-AscH
, ionizing radiation and MnT4MPyP, would result in significant flux of H
O
and pancreatic cancer cytotoxicity. P-AscH
with MnT4MPyP increased the rate of oxidation of P-AscH
and produced radiosensitization in all pancreatic cancer cell lines tested. Three-dimensional (3D) cell cultures demonstrated resistance to P-AscH
, radiation or MnT4MPyP treatments alone; however, combined treatment with P-AscH
and MnT4MPyP resulted in the inhibition of tumor growth, particularly when also combined with radiation. In vivo experiments using a murine model demonstrated an increased rate of ascorbate oxidation when combinations of P-AscH
with MnT4MPyP were given, thus acting as a radiosensitizer. The translational potential was demonstrated by measuring increased ascorbate oxidation ex vivo, whereby MnT4MPyP was added exogenously to plasma samples from patients treated with P-AscH
and radiation. Combination treatment utilizing P-AscH
, manganoporphyrin and radiation results in significant cytotoxicity secondary to enhanced ascorbate oxidation and an increased flux of H
O
. This multimodal approach has the potential to be an effective treatment for pancreatic ductal adenocarcinoma.
Details
- Title: Subtitle
- Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer
- Creators
- Matthew S Alexander - a Department of Surgery, University of Iowa, Iowa City, IowaBrianne R O'Leary - a Department of Surgery, University of Iowa, Iowa City, IowaJustin G Wilkes - a Department of Surgery, University of Iowa, Iowa City, IowaAdrienne R Gibson - b Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IowaBrett A Wagner - b Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IowaJuan Du - a Department of Surgery, University of Iowa, Iowa City, IowaEhab Sarsour - b Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IowaRosa F Hwang - c Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TexasGarry R Buettner - b Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IowaJoseph J Cullen - e Veterans Affairs Medical Center, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Radiation research, Vol.191(1), pp.43-51
- DOI
- 10.1667/RR15189.1
- PMID
- 30376411
- PMCID
- PMC6441967
- NLM abbreviation
- Radiat Res
- ISSN
- 0033-7587
- eISSN
- 1938-5404
- Publisher
- United States
- Grant note
- T32 CA078586 / NCI NIH HHS T32 CA148062 / NCI NIH HHS R01 CA184051 / NCI NIH HHS P01 CA217797 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Surgery; Radiation Oncology
- Record Identifier
- 9984047800002771
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