The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.

Abstract

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 (IC(50), 10-90 micromol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H(2)O(2), 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-kappaB 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.

• Authors: Yu Sun, Basil Rigas
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 20 Pg. 8269-77 (Oct 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18922898 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arsenicals
• NF-kappa B
• Nitric Oxide Donors
• Organophosphates
• Oxides
• Reactive Nitrogen Species
• Reactive Oxygen Species
• phosphoaspirin
• Gold Sodium Thiomalate
• Thioredoxins
• Thioredoxin-Disulfide Reductase
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• Aspirin
• Arsenic Trioxide

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Aspirin (analogs & derivatives, pharmacology)
• Gold Sodium Thiomalate (pharmacology)
• HT29 Cells
• Humans
• MAP Kinase Kinase Kinase 5 (physiology)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Nitric Oxide Donors (pharmacology)
• Organophosphates (pharmacology)
• Oxidation-Reduction
• Oxidative Stress
• Oxides (pharmacology)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors)
• Thioredoxins (physiology)