Abstract
The incidence of pancreatic cancer is increasing as the population ages but treatment advancements continue to lag far behind. The majority of pancreatic cancer patients have a K-ras oncogene mutation causing a shift in the redox state of the cell, favoring malignant proliferation. This mutation is believed to lead to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and superoxide overproduction, generating tumorigenic behavior. Superoxide dismutases (SODs) have been studied for their ability to manage the oxidative state of the cell by dismuting superoxide and inhibiting signals for pancreatic cancer growth. In particular, manganese superoxide dismutase has clearly shown importance in cell cycle regulation and has been found to be abnormally low in pancreatic cancer cells as well as the surrounding stromal tissue. Likewise, extracellular superoxide dismutase expression seems to favor suppression of pancreatic cancer growth. With an increased understanding of the redox behavior of pancreatic cancer and key regulators, new treatments are being developed with specific targets in mind. This review summarizes what is known about superoxide dismutases in pancreatic cancer and the most current treatment strategies to be advanced from this knowledge.
Highlights
Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States [1]
We propose that strategies to scavenge mitochondrial and non-mitochondrial-generated O2 − may prove beneficial in the treatment of pancreatic cancer
The relative lack of progress in therapy for pancreatic adenocarcinoma compared to other common cancers has led to opportunities for innovation and the development of new treatment modalities [9]
Summary
Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States [1]. Therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy is poor, resulting in a dismal 5-year survival of less than 3% [2]. SODs have been shown to inhibit the in vitro and in vivo growth of pancreatic cancer through various intracellular signaling pathways [5,6]. Loss of MnSOD function leads to intracellular signaling supporting pancreatic acinar malignant cellular programming, while loss of extracellular superoxide dismutase (EcSOD) leads to an influx of regulatory pathways supporting pancreatic tumor microenvironments [7,8]. This review will focus on the role of SOD-induced inhibition of tumor growth and propagation, and its potential as a targeted pancreatic cancer therapy.
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