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Modulation of Reactive Oxygen Species in Pancreatic Cancer

Authors' Affiliations: Departments of ¹ Surgery and ² Radiation Oncology, University of Iowa College of Medicine; ³ Holden Comprehensive Cancer Center; and ⁴ Veterans Affairs Medical Center, Iowa City, Iowa

Requests for reprints: Joseph J. Cullen, 4605 JCP, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. Phone: 319-353-8297/319-339-5497; Fax: 319-356-8378; E-mail: joseph-cullen{at}uiowa.edu.

Purpose: The aim of the present study was to compare the effects of the three different forms of the antioxidant enzyme superoxide dismutase [i.e., manganese superoxide dismutase (MnSOD), copper zinc superoxide dismutase (CuZnSOD), and extracellular superoxide dismutase (EcSOD)] on the malignant phenotype of human pancreatic cancer.

Experimental Design: Human pancreatic cancer cell lines were infected with adenoviral vectors containing the cDNAs for three different forms of the antioxidant enzyme SOD. Intratumoral injections of the adenoviral vectors were used in nude mice with human tumor xenografts.

Results: Increases in immunoreactive protein and enzymatic activity were seen after infections with the AdMnSOD, AdCuZnSOD, or AdEcSOD constructs. Increased SOD activity decreased superoxide levels and increased hydrogen peroxide levels. Increasing SOD levels correlated with increased doubling time. Cell growth and plating efficiency decreased with increasing amounts of the adenoviral constructs, with the AdCuZnSOD vector having the greatest effect in decreasing in vitro tumor growth. In contrast, inhibiting endogenous SOD with small interfering RNA increased superoxide levels and promoted tumor growth. Of the three SODs, tumors grew the slowest and survival was increased the greatest in nude mice injected with the AdEcSOD construct.

Conclusions: Scavenging plasma membrane–generated superoxide may prove beneficial for suppression of pancreatic cancer growth.

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