Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress.
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.
Gao
Jianjun
J
Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-5200, USA.
Liu
Xiaoping
X
Rigas
Basil
B
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000008:administration & dosage / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D017491:Genes, APC; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D051176:beta Catenin; D019938:Cyclin D1; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001241:Aspirin