A Novel Mechanism by Which N-(4-hydroxyphenyl)retinamide Inhibits Breast Cancer Cell Growth: The Production of Nitric Oxide
N -(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necro...
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creator | Simeone, Ann-Marie Ekmekcioglu, Suhendan Broemeling, Lyle D Grimm, Elizabeth A Tari, Ana M |
description | N -(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR
induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer.
Apoptotic agents, such as phorbol ester, tumor necrosis factor-α, and peptide hormones, have been shown to increase NO production
in breast cancer cells. Therefore, we hypothesized that the production of NO is vital for 4-HPR to induce apoptosis in breast
cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines
tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced.
To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase
(NOS) inhibitor, N G -monomethyl- l -arginine ( l -NMMA), and 4-HPR. l -NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects
in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both
IFN-γ and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased
apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with
4-HPR, IFN-γ and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis
in breast cancer cells, i.e., by increasing NOS expression to induce NO production. |
format | Article |
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induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer.
Apoptotic agents, such as phorbol ester, tumor necrosis factor-α, and peptide hormones, have been shown to increase NO production
in breast cancer cells. Therefore, we hypothesized that the production of NO is vital for 4-HPR to induce apoptosis in breast
cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines
tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced.
To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase
(NOS) inhibitor, N G -monomethyl- l -arginine ( l -NMMA), and 4-HPR. l -NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects
in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both
IFN-γ and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased
apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with
4-HPR, IFN-γ and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis
in breast cancer cells, i.e., by increasing NOS expression to induce NO production.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>PMID: 12481423</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Antineoplastic Agents - pharmacology ; Apoptosis ; Blotting, Western ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Cell Division - drug effects ; Enzyme Inhibitors - pharmacology ; Fenretinide - pharmacology ; Flow Cytometry ; Humans ; Immunohistochemistry ; Interferon-gamma - metabolism ; Nitric Oxide - metabolism ; Nitric Oxide Synthase - metabolism ; omega-N-Methylarginine - pharmacology ; Tamoxifen - metabolism ; Tamoxifen - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Molecular cancer therapeutics, 2002-10, Vol.1 (12), p.1009-1017</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12481423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Simeone, Ann-Marie</creatorcontrib><creatorcontrib>Ekmekcioglu, Suhendan</creatorcontrib><creatorcontrib>Broemeling, Lyle D</creatorcontrib><creatorcontrib>Grimm, Elizabeth A</creatorcontrib><creatorcontrib>Tari, Ana M</creatorcontrib><title>A Novel Mechanism by Which N-(4-hydroxyphenyl)retinamide Inhibits Breast Cancer Cell Growth: The Production of Nitric Oxide</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>N -(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR
induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer.
Apoptotic agents, such as phorbol ester, tumor necrosis factor-α, and peptide hormones, have been shown to increase NO production
in breast cancer cells. Therefore, we hypothesized that the production of NO is vital for 4-HPR to induce apoptosis in breast
cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines
tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced.
To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase
(NOS) inhibitor, N G -monomethyl- l -arginine ( l -NMMA), and 4-HPR. l -NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects
in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both
IFN-γ and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased
apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with
4-HPR, IFN-γ and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis
in breast cancer cells, i.e., by increasing NOS expression to induce NO production.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Blotting, Western</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cell Division - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fenretinide - pharmacology</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Interferon-gamma - metabolism</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>omega-N-Methylarginine - pharmacology</subject><subject>Tamoxifen - metabolism</subject><subject>Tamoxifen - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo10EFLwzAUB_AiipvTryA5yTwUkjRtU29z6BzMzcPAY0nTVxNpm5mkbsUvb3Hz9N7hx5__e2fBmMQRD3lM2PnfHocpSaJRcOXcJ8aEZ5RcBiNCGSeMRuPgZ4bW5htq9ApSiVa7BhU9eldaKrQOpyxUfWnNod8paPv63oLXrWh0CWjZKl1o79CjBeE8motWgkVzqGu0sGbv1QPaKkBv1pSd9Nq0yFRorb3VEm0OQ8R1cFGJ2sHNaU6C7fPTdv4SrjaL5Xy2ChVl2IdZRAXFBSEEMhJTLtMqoryqqjKpJJYFo6wQQsgojZNYpBmmHCccMllUSSaTaBLcHWN31nx14HzeaCeHmqIF07k8pWmaMY4HeHuCXdFAme-sboTt8_9vDWB6BEp_qL22kMu_oy04EFaqnAw2Jxhn0S9yvXVJ</recordid><startdate>20021001</startdate><enddate>20021001</enddate><creator>Simeone, Ann-Marie</creator><creator>Ekmekcioglu, Suhendan</creator><creator>Broemeling, Lyle D</creator><creator>Grimm, Elizabeth A</creator><creator>Tari, Ana M</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20021001</creationdate><title>A Novel Mechanism by Which N-(4-hydroxyphenyl)retinamide Inhibits Breast Cancer Cell Growth: The Production of Nitric Oxide</title><author>Simeone, Ann-Marie ; Ekmekcioglu, Suhendan ; Broemeling, Lyle D ; Grimm, Elizabeth A ; Tari, Ana M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h240t-932a20b111e91528c7f328fffd6fc0cb424baaac37565a79028068e9cbf69c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Blotting, Western</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cell Division - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fenretinide - pharmacology</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Interferon-gamma - metabolism</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>omega-N-Methylarginine - pharmacology</topic><topic>Tamoxifen - metabolism</topic><topic>Tamoxifen - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Simeone, Ann-Marie</creatorcontrib><creatorcontrib>Ekmekcioglu, Suhendan</creatorcontrib><creatorcontrib>Broemeling, Lyle D</creatorcontrib><creatorcontrib>Grimm, Elizabeth A</creatorcontrib><creatorcontrib>Tari, Ana M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Simeone, Ann-Marie</au><au>Ekmekcioglu, Suhendan</au><au>Broemeling, Lyle D</au><au>Grimm, Elizabeth A</au><au>Tari, Ana M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Mechanism by Which N-(4-hydroxyphenyl)retinamide Inhibits Breast Cancer Cell Growth: The Production of Nitric Oxide</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2002-10-01</date><risdate>2002</risdate><volume>1</volume><issue>12</issue><spage>1009</spage><epage>1017</epage><pages>1009-1017</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>N -(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR
induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer.
Apoptotic agents, such as phorbol ester, tumor necrosis factor-α, and peptide hormones, have been shown to increase NO production
in breast cancer cells. Therefore, we hypothesized that the production of NO is vital for 4-HPR to induce apoptosis in breast
cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines
tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced.
To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase
(NOS) inhibitor, N G -monomethyl- l -arginine ( l -NMMA), and 4-HPR. l -NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects
in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both
IFN-γ and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased
apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with
4-HPR, IFN-γ and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis
in breast cancer cells, i.e., by increasing NOS expression to induce NO production.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>12481423</pmid><tpages>9</tpages></addata></record> |
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source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
subjects | Antineoplastic Agents - pharmacology Apoptosis Blotting, Western Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cell Division - drug effects Enzyme Inhibitors - pharmacology Fenretinide - pharmacology Flow Cytometry Humans Immunohistochemistry Interferon-gamma - metabolism Nitric Oxide - metabolism Nitric Oxide Synthase - metabolism omega-N-Methylarginine - pharmacology Tamoxifen - metabolism Tamoxifen - pharmacology Tumor Cells, Cultured |
title | A Novel Mechanism by Which N-(4-hydroxyphenyl)retinamide Inhibits Breast Cancer Cell Growth: The Production of Nitric Oxide |
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