Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer

John A Cieslak; Robert K Strother; Malvika Rawal; Juan Du; Claire M Doskey; Samuel R Schroeder; Anna Button; Brett A Wagner; Garry R Buettner; Joseph J Cullen

doi:10.1016/j.freeradbiomed.2015.02.018

Back

Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer

Journal article

Peer reviewed

Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer

John A Cieslak, Robert K Strother, Malvika Rawal, Juan Du, Claire M Doskey, Samuel R Schroeder, Anna Button, Brett A Wagner, Garry R Buettner and Joseph J Cullen

Free radical biology & medicine, Vol.83, pp.227-237

06/2015

DOI: 10.1016/j.freeradbiomed.2015.02.018

PMCID: PMC4441864

PMID: 25725418

View Online

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 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 Scavengers - pharmacology

Oxidation-Reduction

Apoptosis - drug effects

Humans

Pancreatic Neoplasms - pathology

Deoxycytidine - pharmacology

Metalloporphyrins - pharmacology

Hydrogen Peroxide - metabolism

Catalase - metabolism

Drug Synergism

Pancreatic Neoplasms - drug therapy

Xenograft Model Antitumor Assays

Animals

Mice, Nude

Oxygen Consumption - drug effects

Ascorbic Acid - pharmacology

Fluorescent Antibody Technique

Antimetabolites, Antineoplastic - pharmacology

Mice

Catalysis

Histones - metabolism

Oxidative Stress - drug effects

Deoxycytidine - analogs & derivatives

Details

Title: Subtitle: Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer
Creators: John A Cieslak - 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
Robert K Strother - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Malvika Rawal - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Juan Du - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Claire M Doskey - Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
Samuel R Schroeder - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Anna Button - Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA
Brett A Wagner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Garry R Buettner - 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
Joseph J Cullen - 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
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.83, pp.227-237
DOI: 10.1016/j.freeradbiomed.2015.02.018
PMID: 25725418
PMCID: PMC4441864
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier BV; United States
Grant note: R01CA169046 / NCI NIH HHS P30 ES005605 / NIEHS NIH HHS T32 CA078586 / NCI NIH HHS T35 HL007485 / NHLBI NIH HHS I01 BX001318 / BLRD VA CA166800 / NCI NIH HHS U01 CA166800 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS CA078586 / NCI NIH HHS
Language: English
Date published: 06/2015
Academic Unit: Surgery; Radiation Oncology
Record Identifier: 9984047850902771

Metrics

19 Record Views

33 Times Cited - Web of Science

See more details