Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.

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.

• Authors: Malvika Rawal, Samuel R Schroeder, Brett A Wagner, Cameron M Cushing, Jessemae L Welsh, Anna M Button, Juan Du, Zita A Sibenaller, Garry R Buettner, Joseph J Cullen
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 16 Pg. 5232-41 (Aug 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23764544 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Metalloporphyrins
• Manganese
• Hydrogen Peroxide
• Catalase
• Superoxide Dismutase
• Ascorbic Acid

Topics

• Animals
• Ascorbic Acid (pharmacology)
• Catalase (metabolism)
• Catalysis (drug effects)
• Cell Line, Tumor
• Humans
• Hydrogen Peroxide (metabolism)
• Manganese (pharmacology)
• Metalloporphyrins (pharmacology)
• Mice
• Mice, Nude
• Oxidation-Reduction (drug effects)
• Oxygen Consumption (drug effects)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Superoxide Dismutase (metabolism)
• Xenograft Model Antitumor Assays