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The Thioredoxin System Mediates Redox-Induced Cell Death in Human Colon Cancer Cells: Implications for the Mechanism of Action of Anticancer Agents

Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York

Requests for reprints: Basil Rigas, Division of Cancer Prevention, Stony Brook University, Life Sciences Building, Room 06, Stony Brook, NY 11794-5200. Phone: 631-632-9035; Fax: 631-632-1992; E-mail: basil.rigas{at}stonybrook.edu.

Key Words: thioredoxin • thioredoxin reductase • reactive oxygen species • cell death • anticancer drugs

Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide–donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC₅₀, 10–90 µmol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H₂O₂, superoxide anion, and peroxynitirte), induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). Nuclear factor-B and mitogen-activated protein kinases were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by small interfering RNA abrogated cell death induced by them. These compounds also inhibited the activity of Trx reductase that reduces oxidized Trx-1, whereas the Trx reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacologic control of cancer. [Cancer Res 2008;68(20):8269–77]

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