Treatment of pancreatic cancer cells with dicumarol induces cytotoxicity and oxidative stress

Anne Lewis; Matthew Ough; Ling Li; Marilyn M Hinkhouse; Justine M Ritchie; Douglas R Spitz; Joseph J Cullen

doi:10.1158/1078-0432.CCR-03-0667

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Treatment of pancreatic cancer cells with dicumarol induces cytotoxicity and oxidative stress

Journal article

Open access

Peer reviewed

Treatment of pancreatic cancer cells with dicumarol induces cytotoxicity and oxidative stress

Anne Lewis, Matthew Ough, Ling Li, Marilyn M Hinkhouse, Justine M Ritchie, Douglas R Spitz and Joseph J Cullen

Clinical cancer research, Vol.10(13), pp.4550-4558

07/01/2004

DOI: 10.1158/1078-0432.CCR-03-0667

PMID: 15240547

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Abstract

quinone oxidoreductase (NQO(1)) catalyzes the two-electron reduction of quinones to hydroquinones. This reaction is believed to prevent the one-electron reduction of quinones that would result in redox cycling with generation of superoxide (O(2)(.-)). We have recently demonstrated that inhibition of NQO(1) with dicumarol increases intracellular O(2)(.-) production and inhibits the in vitro malignant phenotype of pancreatic cancer cells (J. Cullen et al., Cancer Res., 63: 5513-5520, 2003). We hypothesized that inhibition of NQO(1) would increase cell killing, induce oxidative stress, and inhibit in vivo tumor growth. In the human pancreatic cancer cell line MIA PaCa-2, dicumarol decreased cell viability, as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and decreased clonogenic survival. Dicumarol increased the percentage of apoptotic cells in a time-dependent and dose-dependent manner as measured by 3,3'-diaminobenzidine staining and flow cytometry, which was associated with cytochrome c release and poly(ADP-ribose) polymerase cleavage. Dicumarol also induced oxidative stress as evidenced by increased total glutathione and oxidized glutathione, as well as sensitizing to cell killing mediated by menadione. In established orthotopic pancreatic tumors in nude mice, intratumoral injections of dicumarol slowed tumor growth and extended survival. Inhibition of NQO(1) with dicumarol induces cell killing and oxidative stress in pancreatic cancer cells and speculate that dicumarol may prove to be useful in pancreatic cancer therapeutics.

Uncoupling Agents - pharmacology

Oxidative Stress

Glutathione - metabolism

Humans

Hydroquinones - metabolism

Oxygen - metabolism

Dose-Response Relationship, Drug

Pancreatic Neoplasms - drug therapy

Flow Cytometry

Time Factors

Dicumarol - pharmacology

Quinone Reductases - metabolism

Cell Survival

Cytochromes c - metabolism

Enzyme Inhibitors - pharmacology

Blotting, Western

NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors

Vitamin K 3 - metabolism

Phenotype

Poly(ADP-ribose) Polymerases - metabolism

Animals

Mice, Nude

Cell Line, Tumor

Mice

Apoptosis

Electrons

Details

Title: Subtitle: Treatment of pancreatic cancer cells with dicumarol induces cytotoxicity and oxidative stress
Creators: Anne Lewis - Department of Surgery, Radiation Oncology and Holden Comprehensive Cancer Center, and University of Iowa College of Medicine, Iowa City, Iowa, USA
Matthew Ough
Ling Li
Marilyn M Hinkhouse
Justine M Ritchie
Douglas R Spitz
Joseph J Cullen
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.10(13), pp.4550-4558
Publisher: United States
DOI: 10.1158/1078-0432.CCR-03-0667
PMID: 15240547
ISSN: 1078-0432
eISSN: 1557-3265
Grant note: DE-FG02-02ER63447 / NIDCR NIH HHS CA 66081 / NCI NIH HHS HL07485-24 / NHLBI NIH HHS DK 60618 / NIDDK NIH HHS
Language: English
Date published: 07/01/2004
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984051755402771

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