Journal article
Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation
Cancer research (Chicago, Ill.), Vol.73(16), pp.5232-5241
08/15/2013
DOI: 10.1158/0008-5472.CAN-13-0470
PMCID: PMC3745518
PMID: 23764544
Abstract
Renewed interest in using pharmacological ascorbate (AscH
−
) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH
−
action in cancer cells is its ability to act as an electron donor to O
2
for generating H
2
O
2
. We hypothesized that catalytic manganoporphyrins (MnPs) would increase AscH
−
oxidation rates, thereby increasing H
2
O
2
fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP) exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH
−
oxidation as determined by the concentration of ascorbate radical [Asc
•−
] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH
−
synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H
2
O
2
. MnPs increased steady-state concentrations of Asc
•−
upon
ex vivo
addition to whole blood obtained either from mice infused with AscH
−
or patients treated with pharmacologic AscH
−
. Lastly, tumor growth
in vivo
was inhibited more effectively by combining MnT4MPyP with AscH
−
. We concluded that MnPs increase the rate of oxidation of AscH
−
to leverage H
2
O
2
flux and ascorbate-induced cytotoxicity.
Details
- Title: Subtitle
- Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation
- Creators
- Malvika Rawal - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Samuel R Schroeder - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Brett A Wagner - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Cameron M Cushing - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Jessemae Welsh - Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Anna M Button - Holden Comprehensive Cancer Center, Iowa City, Iowa 52242Juan Du - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Zita A Sibenaller - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Garry R Buettner - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242Joseph J Cullen - Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.73(16), pp.5232-5241
- DOI
- 10.1158/0008-5472.CAN-13-0470
- PMID
- 23764544
- PMCID
- PMC3745518
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- P42 ES013661 || ES / National Institute of Environmental Health Sciences : NIEHS U01 CA166800 || CA / National Cancer Institute : NCI R01 GM073929 || GM / National Institute of General Medical Sciences : NIGMS
- Language
- English
- Date published
- 08/15/2013
- Academic Unit
- Surgery; Radiation Oncology
- Record Identifier
- 9984047792202771
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