Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer.
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 indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
John A
JA
Cieslak
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Robert K
RK
Strother
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Malvika
M
Rawal
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Juan
J
Du
Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA.
Claire M
CM
Doskey
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Samuel R
SR
Schroeder
Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
Anna
A
Button
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Brett A
BA
Wagner
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
Garry R
GR
Buettner
Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: joseph-cullen@uiowa.edu.
Joseph J
JJ
Cullen
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002384:Catalysis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016166:Free Radical Scavengers; C468783:H2AX protein, human; D006657:Histones; D008665:Metalloporphyrins; D003841:Deoxycytidine; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D006861:Hydrogen Peroxide; D002374:Catalase; D001205:Ascorbic Acid; D000093542:Gemcitabine