Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer

Free Radical Biology & Medicine
John A CieslakJoseph J Cullen

Abstract

Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an...Continue Reading

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Citations

Oct 27, 2015·Free Radical Biology & Medicine·Artak TovmasyanInes Batinic-Haberle
Aug 22, 2017·Antioxidants·Justin G WilkesJoseph J Cullen
Oct 31, 2018·Radiation Research·Matthew S AlexanderJoseph J Cullen
Jul 19, 2018·Frontiers in Physiology·Margreet C M Vissers, Andrew B Das
Oct 21, 2020·Scientific Reports·Brianne R O'LearyJoseph J Cullen
Jul 25, 2019·Molecular Cancer Research : MCR·Visarut BuranasudjaGarry R Buettner
Jul 14, 2021·Antioxidants & Redox Signaling·Christophe Glorieux, Pedro Buc Calderon

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