Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo
Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulind...
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| Veröffentlicht in: | Biochemical pharmacology 2001-03, Vol.61 (5), p.565-571 |
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| creator | Eli, Yaniv Przedecki, Fiorenza Levin, Galit Kariv, Na’am Raz, Amiram |
| description | Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects
in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells
in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs
in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the
in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (
3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10–20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G
2/M phases, together with an increased percentage of cells at the G
1 phase. Significantly, similar results were seen when indomethacin was given
in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin
in vivo. |
| doi_str_mv | 10.1016/S0006-2952(00)00578-5 |
| format | Article |
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in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells
in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs
in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the
in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (
3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10–20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G
2/M phases, together with an increased percentage of cells at the G
1 phase. Significantly, similar results were seen when indomethacin was given
in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin
in vivo.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/S0006-2952(00)00578-5</identifier><identifier>PMID: 11239499</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Analysis of Variance ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cachexia - prevention & control ; Cell cycle ; Cell Cycle - drug effects ; Cell Division - drug effects ; Cell proliferation ; Cell Survival - drug effects ; Cyclooxygenase 1 ; Cyclooxygenases ; Disease Models, Animal ; General aspects ; Indomethacin ; Indomethacin - pharmacology ; Indomethacin - therapeutic use ; Isoenzymes - drug effects ; Isoenzymes - metabolism ; Lung Neoplasms - prevention & control ; Lung Neoplasms - secondary ; Male ; Medical sciences ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; NSAIDs ; Pharmacology. Drug treatments ; Prostaglandin-Endoperoxide Synthases - drug effects ; Prostaglandin-Endoperoxide Synthases - metabolism ; Tumor cells ; Tumor Cells, Cultured</subject><ispartof>Biochemical pharmacology, 2001-03, Vol.61 (5), p.565-571</ispartof><rights>2001 Elsevier Science Inc.</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-d9ac1d90b24a26f5584bb2936d38bd574c2301b3884cc79970783fc696fb5c1a3</citedby><cites>FETCH-LOGICAL-c455t-d9ac1d90b24a26f5584bb2936d38bd574c2301b3884cc79970783fc696fb5c1a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006295200005785$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=925024$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11239499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Eli, Yaniv</creatorcontrib><creatorcontrib>Przedecki, Fiorenza</creatorcontrib><creatorcontrib>Levin, Galit</creatorcontrib><creatorcontrib>Kariv, Na’am</creatorcontrib><creatorcontrib>Raz, Amiram</creatorcontrib><title>Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects
in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells
in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs
in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the
in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (
3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10–20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G
2/M phases, together with an increased percentage of cells at the G
1 phase. Significantly, similar results were seen when indomethacin was given
in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin
in vivo.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cachexia - prevention & control</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cell proliferation</subject><subject>Cell Survival - drug effects</subject><subject>Cyclooxygenase 1</subject><subject>Cyclooxygenases</subject><subject>Disease Models, Animal</subject><subject>General aspects</subject><subject>Indomethacin</subject><subject>Indomethacin - pharmacology</subject><subject>Indomethacin - therapeutic use</subject><subject>Isoenzymes - drug effects</subject><subject>Isoenzymes - metabolism</subject><subject>Lung Neoplasms - prevention & control</subject><subject>Lung Neoplasms - secondary</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neoplasm Transplantation</subject><subject>NSAIDs</subject><subject>Pharmacology. Drug treatments</subject><subject>Prostaglandin-Endoperoxide Synthases - drug effects</subject><subject>Prostaglandin-Endoperoxide Synthases - metabolism</subject><subject>Tumor cells</subject><subject>Tumor Cells, Cultured</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1DAUhS0EotPCTwBFQqpgkXJtx68VQiMKSJVYAGvL8aMYJfFgZwZ1099eJzMqS1bWPec79tUxQq8wXGHA_P13AOAtUYy8BXgHwIRs2RO0wVLQKnP5FG0ekTN0XsrvZZQcP0dnGBOqOqU26H6bxp3JZo4H3_gQvJ1Lk0ITJ5dGP_8yNk5Nmhrrh6HZ5TTE4Be6SmZyR9ne2cEv5m32pSxWzcz7MeXVL81tTn9X8RDnnNbgOhzSC_QsmKH4l6fzAv28_vRj-6W9-fb56_bjTWs7xubWKWOxU9CTzhAeGJNd3xNFuaOyd0x0llDAPZWys1YoJUBIGixXPPTMYkMv0OXx3rrln70vsx5jWZYzk0_7ogVwQYWECrIjaHMqJfugdzmOJt9pDHopXq_F66VVDaDX4jWrudenB_b96N2_1KnpCrw5AaZYM4RsJhvLI6cIA9JV6sOR8rWMQ_RZFxv9ZL2LuX6Ndin-Z5EHqC6gyQ</recordid><startdate>20010301</startdate><enddate>20010301</enddate><creator>Eli, Yaniv</creator><creator>Przedecki, Fiorenza</creator><creator>Levin, Galit</creator><creator>Kariv, Na’am</creator><creator>Raz, Amiram</creator><general>Elsevier Inc</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20010301</creationdate><title>Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo</title><author>Eli, Yaniv ; Przedecki, Fiorenza ; Levin, Galit ; Kariv, Na’am ; Raz, Amiram</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-d9ac1d90b24a26f5584bb2936d38bd574c2301b3884cc79970783fc696fb5c1a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - therapeutic use</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cachexia - prevention & control</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cell proliferation</topic><topic>Cell Survival - drug effects</topic><topic>Cyclooxygenase 1</topic><topic>Cyclooxygenases</topic><topic>Disease Models, Animal</topic><topic>General aspects</topic><topic>Indomethacin</topic><topic>Indomethacin - pharmacology</topic><topic>Indomethacin - therapeutic use</topic><topic>Isoenzymes - drug effects</topic><topic>Isoenzymes - metabolism</topic><topic>Lung Neoplasms - prevention & control</topic><topic>Lung Neoplasms - secondary</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Neoplasm Transplantation</topic><topic>NSAIDs</topic><topic>Pharmacology. Drug treatments</topic><topic>Prostaglandin-Endoperoxide Synthases - drug effects</topic><topic>Prostaglandin-Endoperoxide Synthases - metabolism</topic><topic>Tumor cells</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Eli, Yaniv</creatorcontrib><creatorcontrib>Przedecki, Fiorenza</creatorcontrib><creatorcontrib>Levin, Galit</creatorcontrib><creatorcontrib>Kariv, Na’am</creatorcontrib><creatorcontrib>Raz, Amiram</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Eli, Yaniv</au><au>Przedecki, Fiorenza</au><au>Levin, Galit</au><au>Kariv, Na’am</au><au>Raz, Amiram</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2001-03-01</date><risdate>2001</risdate><volume>61</volume><issue>5</issue><spage>565</spage><epage>571</epage><pages>565-571</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>Considerable research effort is currently being directed towards understanding the mechanisms mediating the antiproliferative effects of non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, of cyclooxygenase (COX)-2 inhibitors as well. A key question is whether NSAIDs (excluding sulindac) exert their anticarcinogenic effects
in vivo by a mechanism that is dependent on their capacity to inhibit COX activity. Some studies with cultured tumor cells
in vitro have argued against such a linkage, showing that NSAIDs inhibit cell replication and/or augment apoptosis only at concentrations that exceed those required to inhibit COX activities 10- to 100-fold. The significance of these results for the observed anticarcinogenic effects of NSAIDs
in vivo has not yet been evaluated. We addressed this question by comparing, for the same tumor cells, the effects of the NSAID indomethacin on cell growth parameters when the cells were grown in culture to the effects seen in the
in vivo growing tumor in the mouse. Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect (
3H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10–20 μM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G
2/M phases, together with an increased percentage of cells at the G
1 phase. Significantly, similar results were seen when indomethacin was given
in vivo at the low dose of 2 mg per kg/day, which blocked blood platelet COX activity and at the same time produced a delay in tumor growth initiation and attenuation of apparent primary tumor growth as well as growth of lung metastases. These results thus provide strong support for the notion that COX inhibition is a major determinant in the antitumorigenic effect of indomethacin
in vivo.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>11239499</pmid><doi>10.1016/S0006-2952(00)00578-5</doi><tpages>7</tpages></addata></record> |
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| issn | 0006-2952 1873-2968 |
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| subjects | Analysis of Variance Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Antineoplastic agents Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cachexia - prevention & control Cell cycle Cell Cycle - drug effects Cell Division - drug effects Cell proliferation Cell Survival - drug effects Cyclooxygenase 1 Cyclooxygenases Disease Models, Animal General aspects Indomethacin Indomethacin - pharmacology Indomethacin - therapeutic use Isoenzymes - drug effects Isoenzymes - metabolism Lung Neoplasms - prevention & control Lung Neoplasms - secondary Male Medical sciences Membrane Proteins Mice Mice, Inbred C57BL Neoplasm Transplantation NSAIDs Pharmacology. Drug treatments Prostaglandin-Endoperoxide Synthases - drug effects Prostaglandin-Endoperoxide Synthases - metabolism Tumor cells Tumor Cells, Cultured |
| title | Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo |
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