Nitrosulindac (NCX 1102): A new nitric oxide‐donating non‐steroidal anti‐inflammatory drug (NO‐NSAID), inhibits proliferation and induces apoptosis in human prostatic epithelial cell lines

Huguenin, Sandra; Fleury‐Feith, Jocelyne; Kheuang, Laurence; Jaurand, Marie‐Claude; Bolla, Manlio; Riffaud, Jean-Pierre; Chopin, Dominique; Vacherot, Francis

doi:10.1002/pros.20081

Cited by 30 publications

(18 citation statements)

References 39 publications

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“…Similar results have recently been found culturing prostate carcinoma cells in the presence of NO-donating non-steroidal anti-inflammatory drugs like nitrosulindac, NO-ibuprofen or NO-aspirin, which, after enzymatic cleavage release NO intracellularly. Using these compounds the AR-positive cell line LNCaP was found to be considerably more sensitive than AR-negative prostate cell lines like PC3 (Huguenin et al, 2004), although this phenomenon appeared to be time-dependent (Royle et al, 2004). Neoplastic tissue may be considered as a Darwinian microenvironment, where inflammatory products and/or growth factors select for tumor cells, which are able to proliferate signal independently.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

et al. 2006

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Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase (iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNAbinding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

et al. 2006

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“…Previous studies using NO-sulindac demonstrated a cytotoxic and antiproliferative effect on normoxic LNCaP and PC-3 cell lines. 35,36 In these previous studies by Huguenin et al, 36 NO-sulindac was also found to alter the cell cycle, induce mitotic arrest and display pro-apoptotic activity in malignant and benign cell lines. The results of the normoxia experiments in the present study concur with these previous results showing a reduction in PC-3 cell viability in a dose-and time-dependent manner following treatment with NO-sulindac as well as a comparable rate of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

NO‐sulindac inhibits the hypoxia response of PC‐3 prostate cancer cells via the Akt signalling pathway

Stewart

Nanda

Brown

et al. 2008

Intl Journal of Cancer

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Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NOsulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1a (HIF-1a) mRNA using RNAi. Nuclear HIF-1a levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myrAkt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1a translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3. ' 2008 Wiley-Liss, Inc.Key words: hypoxia; prostate cancer; nitric oxide donors; NONSAIDs; AktIn Western Europe and North America, prostate cancer is the commonest cancer and the second most common cause of cancer death in men. In the United Kingdom, prostate cancer accounts for 23% of all new male cancer diagnoses and 13% of male cancerrelated deaths. 1 Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit tumourigenesis in a variety of cancers. [2][3][4] In vitro studies have shown that conventional NSAIDs, at physiological achievable doses, inhibit the proliferation of immortalised human prostate cancer cells. 5 Additionally, meta-analyses of observational studies of men taking regular NSAIDs have reported statistically significant reductions in risk of prostate cancer. 6,7 However, conventional NSAIDs have several side-effects, particularly gastrointestinal bleeding, which limit their use in elderly patients with prostate cancer. In an attempt to reduce the side-effects of traditional NSAIDs, cyclooxygenase-2 inhibitors and nitric oxide (NO • )-donating non-steroidal...

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“…Other authors observed that NO inhibited proliferation and had proapoptotic effects on the epithelial cells of the prostate (15,22).…”

Section: Discussionmentioning

confidence: 92%

“…Various exogenous precursors of nitric oxide were used in the studies on the effects of NO on various tissues and organs in experimental animals, as well as humans (15), including non-steroidal anti-inflammatory drugs (NSAID), (22) so-called donors of nitric oxide (NO-NSAID) (15): NO-inbuprofen (NCX 2111), NOaspirin (NCX 4060) (22), and nitrosulindac (NCX 1102) (15). Other precursors of exogenous nitric oxide also included: sodium nitroprusside (SNP) (2), and S-nitroso-N-acethyl-penicylamine (SNAP) (19).…”

Section: Discussionmentioning

confidence: 99%

Ultrastructure of Renal Tubular Epithelial Cells Of Rat’s Kidneys after Administration of L-Arginine

Pedrycz

Boratyński

Siermontowski³

et al. 2013

Bulletin of the Veterinary Institute in Pulawy

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Abstract. Sixteen white Wistar female rats were divided into two equal groups. Experimental group received per os 40 mg/kg b.w. of L-arginine, every other day for 2 weeks and were decapitated after 3 weeks of the experiment. Control rats received in the same manner 2 ml of distilled water and were decapitated after 3 weeks of the experiment. The renal lesions observed under electron microscope were of focal character and concerned only the experimental group. The tubules with necrotic cells were observed among normal tubules or single normal epithelial cells of the tubular wall. The boundaries between epithelial cells of the tubule wall were blurred. The mitochondria indicated abnormal structure. Numerous lysosomes and peroxysomes with dark, homogenous content were observed. The rough endoplasmic reticulum had widened channels and was focally completely destroyed. The nucleus of damaged cells was most commonly located in one of the cell poles; its shape was changed and visibly smaller than the nuclei of normal cells. Condensation and peripherally located chromatin were noticed. The lesions observed were characteristic for apoptotic cells.

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Nitrosulindac (NCX 1102): A new nitric oxide‐donating non‐steroidal anti‐inflammatory drug (NO‐NSAID), inhibits proliferation and induces apoptosis in human prostatic epithelial cell lines

Abstract: Our results demonstrate the anti-proliferative and proapoptotic activity of nitrosulindac on prostate cancer cell lines and suggest its potential interest for new strategies in the management of prostate cancer.

Cited by 30 publications

References 39 publications

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

NO‐sulindac inhibits the hypoxia response of PC‐3 prostate cancer cells via the Akt signalling pathway

Ultrastructure of Renal Tubular Epithelial Cells Of Rat’s Kidneys after Administration of L-Arginine

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