Positional Isomerism Markedly Affects the Growth Inhibition of Colon Cancer Cells by Nitric Oxide-Donating Aspirin in Vitro and in Vivo

Kashfi, Khosrow; Borgo, Simona; Williams, Jennie L.; Chen, Jie; Gao, Jianjun; Glekas, Athanasios; Benedini, Francesca; Soldato, Piero Del; Rigas, Basil

doi:10.1124/jpet.104.075994

Cited by 79 publications

(76 citation statements)

References 15 publications

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“…To a first approximation, NO-NSAIDs have a strong cell growth inhibitory effect, which is the end result of three individual effects: inhibition of cell proliferation, induction of apoptosis and deceleration of cell cycle phase transitions [19,[29][30][31]. The most detailed study on the induction of apoptosis was conducted by Gao et al [32], whose work on NO-ASA highlighted three important aspects of this effect: a) the first recognizable effect was the induction of oxidative stress; b) this was followed by activation of the intrinsic apoptosis pathway; and c) inhibition of Wnt signaling was a major component of the proapoptotic effect of NO-ASA.…”

Section: Evidence For the Anticancer Effect Of No-nsaidsmentioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

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Section: Evidence For the Anticancer Effect Of No-nsaidsmentioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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“…Interestingly, the pharmacologic profile of NO-ASA seems to be dependent on the positional isomerism, with different isomers showing varying efficacies in different disease backgrounds (20). The para-isomer, for example, was shown to be a very potent inducer of apoptosis in colon cancer cell lines and in an intestinal cancer mouse model (21). The same group demonstrated a disruption of the b-catenin/Tcf/ Lef-1 complex as a potential mechanism of NO-ASA action in colon cancer (13,22), a tumor where 100% of cases show an aberrant activation of Wnt/b-catenin/Tcf/Lef-1 signaling due to an APC or a CTNNB1 (b-catenin) mutation.…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide–Donating Acetylsalicylic Acid Induces Apoptosis in Chronic Lymphocytic Leukemia Cells and Shows Strong Antitumor Efficacy In vivo

Razavi¹,

Gehrke²,

Gandhirajan³

et al. 2011

Clinical Cancer Research

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Purpose: Nitric oxide-donating acetylsalicylic acid (NO-ASA) has been shown to possess an antineoplastic effect in Wnt-/b-catenin-active cancers. As chronic lymphocytic leukemia (CLL) cells exhibit aberrantly active Wnt signaling, we investigated the effect of the para-isomer of NO-ASA on CLL cell survival in vitro and in a CLL-like xenograft mouse model.Experimental Design: Apoptosis in primary CLL cells was determined by flow cytometric annexin V-FITC (fluorescein isothiocyanate)/PI (propidium iodide) staining and immunoblotting of caspases, poly(ADP-ribose) polymerase (PARP), and antiapoptotic proteins. Interference of NO-ASA with Wnt/ b-catenin signaling was analyzed through immunoblots of different pathway members. Influence of caspase activation was investigated by pretreatment with a pan-caspase inhibitor. CLL-like JVM3 cells were subcutaneously inoculated into irradiated nude mice that were treated with 100 mg of para-NO-ASA/kg of body weight p.o. (by mouth) for 21 days.Results: para-NO-ASA induced apoptosis in CLL cells with an LC 50 (lethal concentration) of 8.72 þ 0.04 mmol/L, whereas healthy blood cells were not affected. Furthermore, the compound induced caspase 9, caspase 3, and PARP cleavage. In addition, cleavage of b-catenin and downregulation of b-catenin/ lymphoid enhancer factor (Lef)-1 targets was observed. para-NO-ASA demonstrated strong antitumor efficacy in the xenograft mouse model with a tumor inhibtion rate of 83.4%. During therapy, no gross toxicity could be observed.Conclusions: para-NO-ASA selectively induces apoptosis in primary CLL cells and efficiently reduces tumor growthin a CLL-likexenograftmodel. As NO-ASA is orally available and is generally welltolerated, para-NO-ASA might be a promising new compound for CLL therapy. Clin Cancer Res; 17(2); 286-93. Ó2010 AACR.

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“…Similarly, the mechanism of their enhanced potency has not been fully clarified. Converging lines of evidence underscore the vital role of the NO-releasing moiety, and a recent report showed an excellent correlation between the amount of NO released by NO-NSAIDs and their ability to inhibit the growth of cultured colon cancer cells (6). In vitro data have shown that NO-NSAIDs have been invariably more potent than their parent compounds, although their enhanced potency ranged between 10-to >1,000-fold (7).…”

Section: Introductionmentioning

confidence: 99%

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

Rao

Reddy

Steele

et al. 2006

Molecular Cancer Therapeutics

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Nitric oxide -releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NOindomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Sevenweek-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NOaspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' (P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (52 -75% inhibition) and formation of prostaglandin E 2 (PGE 2 ), PGF 2A , and 6-keto-PGF 1A , and TxB 2 from arachidonic acid (53 -77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and B-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and B-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials. [Mol Cancer Ther 2006;5(6):1530-8]

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Positional Isomerism Markedly Affects the Growth Inhibition of Colon Cancer Cells by Nitric Oxide-Donating Aspirin in Vitro and in Vivo

Cited by 79 publications

References 15 publications

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Nitric Oxide–Donating Acetylsalicylic Acid Induces Apoptosis in Chronic Lymphocytic Leukemia Cells and Shows Strong Antitumor Efficacy In vivo

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

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