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Abstract

Ascorbic acid (AA) has been reported to inhibit tumor cell growth through the generation of extracellular hydrogen peroxide (H₂O₂). However, the clinical utility of AA has been limited by relatively low potency and in vivo efficacy. This study reports that the metalloporphyrin, Mn(III) tetrakis(N-methylpyridinium-2-yl)porphyrin⁵⁺ (MnTMPyP), has a potent synergistic cytotoxic effect when combined with AA in a variety of cancer cell lines. In the presence of MnTMPyP, the concentration of AA required to inhibit cancer cell growth was markedly reduced. In vitro (cell-free) experiments demonstrated that AA alone enhanced the Fenton reaction that produces cytotoxic hydroxyl radical (HO^•); however, this reaction was limited by the low rate by which AA generates H₂O₂ (Fenton reaction substrate) from O₂. MnTMPyP catalyzed H₂O₂ generation through the AA-facilitated Mn(II ⇔ III)TMPyP redox cycle and thereby markedly potentiated the Fenton reaction. Accordingly, MnTMPyP and AA resulted in increased cellular levels of H₂O₂ and HO^• in cancer cells, which mediate the synergistic cytotoxicity of this combined treatment. This effect was inhibited by cellular enzymes that metabolize H₂O₂, such as catalase and glutathione peroxidase, suggesting that selective killing of cancer cells deficient in such enzymes can be achieved in vivo.

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Metalloporphyrin Synergizes with Ascorbic Acid to Inhibit Cancer Cell Growth Through Fenton Chemistry

Abstract

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