Manganoporphyrins Increase Ascorbate-Induced Cytotoxicity by Enhancing H2O2 Generation
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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 O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH− oxidation rates, thereby increasing H2O2 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 H2O2. 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−. Finally, 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 H2O2 flux and ascorbate-induced cytotoxicity. Cancer Res; 73(16); 5232–41. ©2013 AACR.
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Many cell-culture experiments show that pharmacological ascorbate makes extracellular H2O2 that can directly destroy cancer cells.
“Numerous in vitro cell culture studies have shown that pharmacological ascorbate produces extracellular H2O2, which can directly kill cancer cells26–28.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [28]
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- Authors
- Rawal, M., Schroeder, S. R., Wagner, B. A., Cushing, C. M., Welsh, J. L., Button, A. M., Du, J., Sibenaller, Z. A., Buettner, G. R., & Cullen, J. J.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Cullen, Joseph J.
- ORCID
- Venue
- Cancer Research
- Published
- 2013-08-13
- Volume
- 73
- Issue
- 16
- Pages
- 5232-5241
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3745518
- OpenAlex
- W1978059781
- Cited by
- 78
- References
- 38
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 5 · 2015: 13 · 2014: 4 · 2013: 6
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001318)
- National Cancer Institute (U01CA166800, R01CA169046, CA166800, P30CA086862)
- National Institute of General Medical Sciences (R01GM073929, GM073929)
- National Institute of Environmental Health Sciences (P42ES013661, P30ES005605)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- pharmacological ascorbate, ascorbyl radical, hydrogen peroxide production, oxidative cytotoxicity, MnTBAP, pancreatic cancer, catalase, tumor growth inhibition, whole blood
- MeSH terms
- Animals, Ascorbic Acid, Catalase, Catalysis, Humans, Hydrogen Peroxide, Manganese, Metalloporphyrins, Mice, Nude, Oxidation-Reduction, Oxygen Consumption, Pancreatic Neoplasms, Superoxide Dismutase, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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