Cargando…

Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin

BACKGROUND: The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing mo...

Descripción completa

Detalles Bibliográficos
Autores principales: Nath, Niharika, Liu, Xiaoping, Jacobs, Lloydine, Kashfi, Khosrow
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656819/
https://www.ncbi.nlm.nih.gov/pubmed/23690679
http://dx.doi.org/10.2147/DDDT.S43771
_version_ 1782270056976089088
author Nath, Niharika
Liu, Xiaoping
Jacobs, Lloydine
Kashfi, Khosrow
author_facet Nath, Niharika
Liu, Xiaoping
Jacobs, Lloydine
Kashfi, Khosrow
author_sort Nath, Niharika
collection PubMed
description BACKGROUND: The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer. METHODS: We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3. RESULTS: NBS-242 inhibited the growth of A-431 cancer cells, being ~15-fold more potent than flurbiprofen and up to 5-fold more potent than NO-flurbiprofen with an aliphatic spacer, the half maximal inhibitory concentrations (IC(50)) for growth inhibition being 60 ± 4 μM, 320 ± 20 μM, and 880 ± 65 μM for NBS-242, NO-flurbiprofen, and flurbiprofen, respectively. This effect was associated with inhibition of proliferation, accumulation of cells in the G(0)/G(1) phase of the cell cycle, and an increase in apoptotic cell population. NBS-242 cleaved β-catenin both in the cytoplasm and the nucleus of A-431 cells. NBS-242 activated caspase-3 whose activation was reflected in the cleavage of procaspase-3. To test the functional consequence of β-catenin cleavage, we determined the expression of cyclin D1, a Wnt-response gene. NBS-242 reduced cyclin D1 levels in a concentration dependent manner. CONCLUSION: These findings establish a strong inhibitory effect of NBS-242 in A-431 human epidermoid carcinoma cells. NBS-242 modulates parameters that are important in determining cellular mass.
format Online
Article
Text
id pubmed-3656819
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-36568192013-05-20 Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin Nath, Niharika Liu, Xiaoping Jacobs, Lloydine Kashfi, Khosrow Drug Des Devel Ther Original Research BACKGROUND: The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer. METHODS: We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3. RESULTS: NBS-242 inhibited the growth of A-431 cancer cells, being ~15-fold more potent than flurbiprofen and up to 5-fold more potent than NO-flurbiprofen with an aliphatic spacer, the half maximal inhibitory concentrations (IC(50)) for growth inhibition being 60 ± 4 μM, 320 ± 20 μM, and 880 ± 65 μM for NBS-242, NO-flurbiprofen, and flurbiprofen, respectively. This effect was associated with inhibition of proliferation, accumulation of cells in the G(0)/G(1) phase of the cell cycle, and an increase in apoptotic cell population. NBS-242 cleaved β-catenin both in the cytoplasm and the nucleus of A-431 cells. NBS-242 activated caspase-3 whose activation was reflected in the cleavage of procaspase-3. To test the functional consequence of β-catenin cleavage, we determined the expression of cyclin D1, a Wnt-response gene. NBS-242 reduced cyclin D1 levels in a concentration dependent manner. CONCLUSION: These findings establish a strong inhibitory effect of NBS-242 in A-431 human epidermoid carcinoma cells. NBS-242 modulates parameters that are important in determining cellular mass. Dove Medical Press 2013-05-06 /pmc/articles/PMC3656819/ /pubmed/23690679 http://dx.doi.org/10.2147/DDDT.S43771 Text en © 2013 Nath et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
spellingShingle Original Research
Nath, Niharika
Liu, Xiaoping
Jacobs, Lloydine
Kashfi, Khosrow
Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title_full Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title_fullStr Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title_full_unstemmed Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title_short Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
title_sort flurbiprofen benzyl nitrate (nbs-242) inhibits the growth of a-431 human epidermoid carcinoma cells and targets β-catenin
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656819/
https://www.ncbi.nlm.nih.gov/pubmed/23690679
http://dx.doi.org/10.2147/DDDT.S43771
work_keys_str_mv AT nathniharika flurbiprofenbenzylnitratenbs242inhibitsthegrowthofa431humanepidermoidcarcinomacellsandtargetsbcatenin
AT liuxiaoping flurbiprofenbenzylnitratenbs242inhibitsthegrowthofa431humanepidermoidcarcinomacellsandtargetsbcatenin
AT jacobslloydine flurbiprofenbenzylnitratenbs242inhibitsthegrowthofa431humanepidermoidcarcinomacellsandtargetsbcatenin
AT kashfikhosrow flurbiprofenbenzylnitratenbs242inhibitsthegrowthofa431humanepidermoidcarcinomacellsandtargetsbcatenin