Nitric Oxide-Donating Aspirin Inhibits Colon Cancer Cell Growth via Mitogen-Activated Protein Kinase Activation

Abstract

Nitric oxide-donating aspirin (NO-aspirin), representing a new concept in the development of more efficacious nonsteroidal anti-inflammatory drugs, consists of traditional aspirin bearing -ONO 2 , which releases NO. Conventional aspirin prevents human colon cancer, but its toxicity precludes its application as a chemopreventive agent. NO-aspirin seems safer and in cultured cancer cells it is Ͼ1000-fold more potent than aspirin. To determine the mechanism by which NO-aspirin inhibits cell growth, we studied its effect on mitogen-activated protein kinase (MAPK) signaling in HT-29 human colon cancer cells. NO-aspirin stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 and Akt only marginally. The greatest increases in phosphorylation were seen in cJun NH 2 -terminal kinase (JNK) and p38 MAP kinases, which were observed as early as 5 min and after 1 h of treatment, averaged more than 10-fold over control. The activation of JNK and p38 was accompanied by large increases in the phosphorylation of the downstream transcription factors cJun and activating transcription factor 2 (ATF-2). We used specific MAPK inhibitors, small interfering (siRNA) gene silencing methods, and dominant-negative cJun to determine the relevance of these phosphorylation events to the ability of NO-aspirin to inhibit colon cancer cell growth. Only the dual inhibitor of p38 and JNK and the use of combined siRNA silencing of p38 and cJun abrogated the ability of NO-aspirin to block cell growth. Our data indicate that NO-aspirin is dependent on both the p38 and the JNK MAP kinase pathways for its ability to inhibit the growth of colon cancer cells.

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

“…Numerous evidences revealed strong antineoplastic properties of NSAIDs modified by covalent attachment of NO (6,8,9,12,30). In this study, we showed for the first time that chemical modification of parental isoxazole acetic acid derivative VGX-1027 created a qualitatively new NOdonating compound possessed strong antitumor potential.…”

Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate–Dependent Activation of c-Jun NH2-Terminal Kinase

“…Guggulsterone has been shown to suppress growth of cancer cells including acute myeloid leukemia and PC-3 human prostate cancer cell lines by causing apoptosis (32,34) but the sequence of events leading to cell death is poorly defined. To gain insights into the mechanism of guggulsterone-induced apoptosis, we determined its effect on activating phosphorylations of JNK1/2 (Thr 183 /Tyr 185 ), p38 MAPK (Tyr 182 ), and ERK1/2 (Tyr 204 ), which are implicated in regulation of cell survival and apoptosis by different stimuli including various cancer preventive agents (35)(36)(37)(38)(39)(40). Figure 1A (Fig.…”

Nitric oxide–releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets

“…Of note, recent in vitro work has indicated that NOaspirin has a major effect on the mitogen-activated protein kinase pathway affecting the activation of c-Jun and activating transcription factor-2, two proteins that participate in the formation of the activator protein complex (46).…”