Surgery

Joseph Cullen, MD

Portrait

Chief, Surgical Services, VA Medical Center
Professor of Surgery  - Gastrointestinal, Minimally-invasive and Bariatric Surgery

Contact Information

Primary Office: 1528 JCP
Iowa City, IA 52242
Primary Office Phone: 319-353-8297

Email: joseph-cullen@uiowa.edu

Education

MD, University of Iowa
BA, Loras College, Dubuque, IA

Residency, General Surgery, University of Iowa
Fellowship, Digestive Disease, NIH Fellow, Mayo Clinic

Licensure and Certifications

Iowa Medical License (permanent), Iowa Board of Medicine
Board Certified, General Surgery, American Board of Surgery

Education/Training Program Affiliations

Biosciences Graduate Program
Free Radical and Radiation Biology Graduate Program
Interdisciplinary Graduate Program in Translational Biomedicine
Medical Scientist Training Program

Research Summary

Our research laboratory is focused on developing treatments for pancreatic cancer. Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Our efforts are directed in two specific areas. 1. Dicumarol is a naturally occurring anticoagulant derived from coumarin, which is obtained from the sweet clover (Melilotus alba). Though such coumarin compounds as dicumarol have been utilized in cancer therapy, little is known about the mechanism of action of these drugs. Recent studies from our group have demonstrated that dicumarol induces cytotoxicty and oxidative stress in pancreatic cancer cells and this cytotoxicity appears to be more prominent in transformed vs. normal human fibroblasts. Mitochondria have been hypothesized to be the site of proxidant production during dicumarol treatment since dicumarol is thought to affect quinone-mediated electron transfer reactions leading to the production of superoxide (O2 .- ), and hydrogen peroxide (H2O2). Dicumarol-induced oxidative stress could represent a difference between tumor cell and normal cell mitochondrial metabolism amenable to manipulations designed to improve cancer therapy. To gain a mechanistic understanding of dicumarol-induced oxidative stress in pancreatic cancer cells, our laboratory investigates the hypothesis that mitochondrial production of reactive oxygen species (superoxide, hydrogen peroxide, and/or organic hydroperoxides) mediates the increased susceptibility of pancreatic cancer cells to dicumarol-induced metabolic oxidative stress, relative to normal human cells. 2. The objective of our second set of studies is to determine if antioxidant enzymes can be modulated for therapeutic purposes in pancreatic cancer. Signaling through the K-ras pathway in pancreatic cancer is related to treatment resistance. K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Ras overexpression leads to increased plasma membrane-generated superoxide, which could be one mechanism regulating cell growth contributing to tumor progression. The objective of our studies is to determine if plasma membrane-generated superoxide can be modulated for therapeutic purposes in pancreatic cancer. Our central hypothesis is that scavenging of superoxide generated from the plasma membrane inhibits pancreatic cancer growth. Our hypothesis has been formulated on the basis of data demonstrating that scavenging of superoxide with the antioxidant enzymes extracellular superoxide dismutase (ECSOD) and copper/zinc superoxide dismutase (CuZnSOD), and small molecule superoxide scavengers have a strong tumor suppressive effect in pancreatic cancer. It is our expectation that the results will facilitate the discovery and development of targeted therapeutics against pancreatic cancer. Our laboratory is currently partially funded by grants from the National Institutes of Health.

Selected Publications

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Sibenaller Z, Welsh J, Du C, Witmer J, Schrock H, Du J, Buettner G, Goswami P, Cieslak III J, Cullen J.  Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer.  Free Radical Biology and Medicine.  2014 April. 69:357-66.
[PubMed]

Rawal M, Schroeder S, Wagner B, Cushing C, Welsh J, Button A, Du J, Sibenaller Z, Buettner G, Cullen J.  Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.  Cancer Research.  2013 August 15. 73(16):5232-5241.
[PubMed]

Du J, Nelson E, Simons A, Olney K, Moser J, Schrock H, Wagner B, Buettner G, Smith B, Teoh M, Tsao M, Cullen J.  Regulation of pancreatic cancer growth by superoxide.  Molecular Carcinogenesis.  2013 July. 52(7):555-567.
[PubMed]

Welsh J, Wagner B, van 't Erve T, Zehr P, Berg D, Halfdanarson T, Yee N, Bodeker K, Du J, Roberts L, Drisko J, Levine M, Buettner G, Cullen J.  Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial.  Cancer Chemotherapy and Pharmacology.  2013 March. 71(3):765-775.
[PubMed]

Du J, Cullen J, Buettner G.  Ascorbic acid: chemistry, biology and the treatment of cancer.  BBA Reviews on Cancer.  2012 December. 1826(2):443-457.
[PubMed]

Du J, Liu J, Smith B, Tsao M, Cullen J.  Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer.  Cancer Gene Therapy.  2011 February. 18(2):135-143.
[PubMed]

Du J, Martin S, Levine M, Wagner B, Buettner G, Wang S, Taghiyev A, Du C, Knudson C, Cullen J.  Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.  Clinical Cancer Research.  2010 January 15. 16(2):509-520.
[PubMed]

Weydert C, Cullen J.  Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue.  Nature Protocols.  2010 January. 5(1):51-66.
[PubMed]

Sun W, Kalen A, Smith B, Cullen J, Oberley L.  Enhancing the antitumor activity of adriamycin and ionizing radiation.  Cancer Research.  2009 May 15. 69(10):4294-4300.
[PubMed]

Du J, Daniels D, Asbury C, Venkataraman S, Liu J, Spitz D, Oberley L, Cullen J.  Mitochondrial production of reactive oxygen species mediate dicumarol-induced cytotoxicity in cancer cells.  Journal of Biological Chemistry.  2006 December 8. 281(49):37416-37426.
[PubMed]

Date Last Modified: 06/07/2014 - 21:56:23