Abstract |
Nitric oxide-donating aspirin ( NO-ASA) is a promising chemoprevention agent against colon cancer and other cancers. It consists of traditional ASA to which a NO-releasing moiety is bound through a spacer. NO-ASA inhibits colon cancer cell growth several hundred times more potently than does ASA. In Min mice, NO-ASA inhibited intestinal carcinogenesis without affecting cell proliferation. Thus, we examined whether NO-ASA's most important cell kinetic effect is the induction of apoptosis. After confirming induction of apoptosis in Min mice, we studied the underlying mechanism in human colon adenocarcinoma cells. NO-ASA's spacer formed a conjugate with glutathione, depleting glutathione stores. This induced oxidative stress (increased intracellular levels of peroxides and O(2)(.-)) leads to apoptosis by activating the intrinsic apoptosis pathway. NO-ASA disrupted adherens junctions by inducing cleavage of beta- and gamma-catenin, resulting in cell detachment. NO-ASA inhibited Wnt signaling by a dual mechanism: at low concentrations it blocked the formation of beta-catenin/Tcf complexes (dominant mechanism), and at higher concentrations it also cleaved beta-catenin. These findings provide a mechanism of action by a potent chemopreventive agent, underscore the significance of these pathways in regulating cell death in the context of cancer chemoprevention, and present a paradigm for developing agents with enhanced cancer cell growth inhibitory properties.
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Authors | Jianjun Gao, Xiaoping Liu, Basil Rigas |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 102
Issue 47
Pg. 17207-12
(Nov 22 2005)
ISSN: 0027-8424 [Print] United States |
PMID | 16282376
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antineoplastic Agents
- Nitric Oxide Donors
- beta Catenin
- Cyclin D1
- CASP3 protein, human
- Casp3 protein, mouse
- Caspase 3
- Caspases
- Aspirin
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Topics |
- Adenocarcinoma
(drug therapy, metabolism, pathology)
- Adherens Junctions
(drug effects, metabolism)
- Animals
- Antineoplastic Agents
(administration & dosage, metabolism)
- Apoptosis
(drug effects)
- Aspirin
(administration & dosage, metabolism)
- Caspase 3
- Caspases
(biosynthesis, physiology)
- Cell Line, Tumor
- Colonic Neoplasms
(drug therapy, metabolism, pathology)
- Cyclin D1
(metabolism)
- Down-Regulation
(drug effects)
- Genes, APC
- Humans
- Hydrolysis
- Mice
- Mice, Inbred C57BL
- Nitric Oxide Donors
(administration & dosage, metabolism)
- Oxidative Stress
(drug effects)
- Signal Transduction
(drug effects)
- beta Catenin
(metabolism)
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