Emerging novel mechanisms of action for nitric oxide in cancer progression

Glynn, Sharon A.

doi:10.1016/j.cophys.2019.03.010

Cited by 9 publications

(4 citation statements)

References 46 publications

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“…13 C-NMR (101 MHz, CDCl 3 ) δ 169.3, 168.4, 157.9, 151.8, 138.3, 138.0, 137.9, 137.3, 135.9, 134.8, 130.2, 129.9, 129.8, 129.3, 129.2, 128.6, 128.5, 128.4, 126.9, 120.7, 120.2, 110.6, 67.2, 51.7, 28.7, and 21.0. MS (IE, 70 eV) m/z](%): 568 (M + -NH-t-butyl, 0.1); 540 (40); 345 (71); 316 (33); 196 (54); 121 (100); 91 (39); 77 (22); and 57 (14). HRMS (ESI+): calculated for.…”

Section: N-(1-(tert-butylaminocarbonyl)-1-phenylmethyl)-n-(4-methylph...mentioning

confidence: 99%

“…This depends mainly on its intracellular concentration but also on the microenvironment, cell type, and the exposure time to ·NO. Some studies suggest that at high levels this radical can exert its antitumor activity through various mechanisms [ 22 , 23 ]. Among the structures capable of releasing ·NO, furoxans are a widely used example in medicinal chemistry [ 24 ], especially in the search for anticancer agents [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions

et al. 2022

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Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid generation of molecular diversity and complexity. We herein report the use of Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions under efficient, safe, and environmentally friendly conditions to synthesize a small collection of nitric-oxide-releasing molecules. The in vitro antiproliferative activity of the synthesized compounds was measured against two different human cancer cell lines, LNCaP (prostate) and T24 (bladder). Almost all compounds displayed antiproliferative activity against both cancer cell lines, providing lead compounds with nanomolar GI50 values against the cancer bladder cell line with selectivity indices higher than 10.

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Section: N-(1-(tert-butylaminocarbonyl)-1-phenylmethyl)-n-(4-methylph...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions

et al. 2022

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“…In addition, overexpression of NOSTRIN curtailed cell invasion and gemcitabine-induced apoptotic cell death in human pancreatic cancer cell line [ 15 ]. NOSTRIN’s ability to sequester eNOS and consequently its dampening effect on NO production by endothelial cells has been implicated in cancer progression [ 16 ]. Interestingly, combined use of NOS inhibitors with 5-fluorouracil showed enhanced inhibition of cell proliferation and migration in CRC cell lines [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Nitric-Oxide Synthase trafficking inducer (NOSTRIN) is an emerging negative regulator of colon cancer progression

et al. 2022

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Background NOSTRIN, abundantly expressed in colon, was reported to be anti-angiogenic, anti-invasive and anti-inflammatory. NOSTRIN expression was inversely related to survival of pancreatic ductal adeno-carcinoma patients. Yet its function and regulatory mechanism in CRC remains elusive. Methods NOSTRIN’s influence on EMT of CRC cells were analysed using realtime PCR array containing the functional EMT-transcriptome followed by western blotting. Regulation of oncogenic potential of CRC cells by NOSTRIN was elucidated using soft agar colony formation, trans-well invasion, wound healing and colonosphere formation assays. Biochemical assays were used to reveal mechanism of NOSTRIN function. Human CRC tissue array was used to test NOSTRIN mark in control and CRC disease stages. Results We showed here that CRC cell lines with less NOSTRIN expression has more invasive and migratory potential. NOSTRIN affected EMT-associated transcriptome of CRC cells by down regulating 33 genes that were functionally annotated to transcription factors, genes important for cell growth, proliferation, migration, cell adhesion and cytoskeleton regulators in CRC cells. NOSTRIN over-expression significantly reduced soft agar colony formation, wound healing and cell invasion. In line with this, RNA interference of Nostrin enhanced metastatic potential of CRC cells. Furthermore, stable overexpression of NOSTRIN in CRC cell line not only curtailed its ability to form colonosphere but also decreased expression of stemness markers CD133, CD44 and EpCAM. NOSTRIN’s role in inhibiting self-renewal was further confirmed using BrdU incorporation assay. Interestingly, NOSTRIN formed immune-complex with Cdk1 in CRC cells and aided in increase of inhibitory Y15 and T14 phosphorylation of Cdk1 that halts cytokinesis. These ex vivo findings were substantiated using human colon cancer tissue array containing cDNAs from patients’ samples with various stages of disease progression. Significant decrease in NOSTRIN expression was found with initiation and progression of advanced colon cancer disease stages. Conclusion We illustrate function of a novel molecule, NOSTRIN in curtailing EMT and maintenance of CRC cell stemness. Our data validates importance of NOSTRIN mark during onset and disease progression of CRC indicating its diagnostic potential.

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“…On the other hand, when inappropriate and excessive NO production occurs, NO takes on a pathological role, being associated with the development of different diseases, such as neurological and inflammatory diseases, atherosclerosis, pain and cancer. [2][3][4] NO is generated as a product of the enzymatic oxidation of l-Arg to l-Cit, by the heme-containing enzyme nitric oxide synthase (NOS). [5] There are three distinct isoforms of NOS: the endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutive and calcium dependent" and catalyze the production of low and pulsating NO levels.…”

Section: Introductionmentioning

confidence: 99%

A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

et al. 2020

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Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties , by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the bloodbrain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated.

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Emerging novel mechanisms of action for nitric oxide in cancer progression

Cited by 9 publications

References 46 publications

Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions

Greener Synthesis of Antiproliferative Furoxans via Multicomponent Reactions

Nitric-Oxide Synthase trafficking inducer (NOSTRIN) is an emerging negative regulator of colon cancer progression

A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

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