Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress

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 ␤-and ␥-catenin, resulting in cell detachment. NO-ASA inhibited Wnt signaling by a dual mechanism: at low concentrations it blocked the formation of ␤-catenin͞Tcf complexes (dominant mechanism), and at higher concentrations it also cleaved ␤-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.NO-aspirin ͉ cell death ͉ Wnt signaling ͉ chemoprevention

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

“…NO release triggered the production of reactive radicals and, as a consequence, led to reduction of cell viability that was further verified by the antioxidant-N-acetylcysteine treatment. This is consistent with the ability of NO-donating aspirin to induce apoptosis in human colon cancer cells through induction of oxidative stress (10). However, it was recently shown that antitumor property of NO-NSAIDs was not the consequence of attached NO but could be ascribed to the NO carrier (40).…”

“…Thus, it was shown that NOaspirin was capable to induce apoptosis in colon cancer cells, whereas the other drug, NO-sulindac, was responsible for apoptotic death of bladder and prostate carcinoma (9,10). Several evidences indicate that the capacity of the tumor cells to develop resistance to pharmacologically induced apoptosis plays a key role in determining their resistance to chemotherapy (32).…”

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

“…An increase in the population of Annexin V þ and PI þ cells was observed at higher dose of QCA. It is well known that ROS production and apoptosis are closely related and activation of caspase-3 is one of hallmark consequences of GSH depletion 35,36 . Therefore, the superior apoptosis-inducing potential of QCA is attributed to the combined effects of GSH-depleting QM and ROS-generating cinnamaldehyde.…”

Possible Relation between the NOS3 Gene GLU298ASP Polymorphism and Bladder Cancer in Turkey

“…On the other hand, there are also studies suggesting the protective role of NO such as reduction of tumor cell adhesion to endothelium (Kong et al, 1996) increasing the blood flow (Dhar et al, 2003) and modulation of apoptosis. (Choi et al, 2002;Fabbri et al, 2005;Gao et al, 2005;Lu et al, 2006).…”