Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells
The bisindole indirubin has been described, more than 30 years ago, as being clinically active in the treatment of human chronic myelocytic leukaemia. However, the underlying mechanism of action has remained unclear. We have reported previously that indirubin and its analogues are potent and selecti...
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| Veröffentlicht in: | British journal of cancer 2001, Vol.84 (2), p.283-289 |
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| creator | Marko, D Schätzle, S Friedel, A Genzlinger, A Zankl, H Meijer, L Eisenbrand, G |
| description | The bisindole indirubin has been described, more than 30 years ago, as being clinically active in the treatment of human chronic myelocytic leukaemia. However, the underlying mechanism of action has remained unclear. We have reported previously that indirubin and its analogues are potent and selective inhibitors of cyclin-dependent kinases (CDK). In this study, we investigated the influence of indirubin and derivatives on CDK1/cyclin B kinase in human tumour cells at concentrations known to induce growth inhibition. Cells of the mammary carcinoma cell line MCF-7, synchronized by serum deprivation, after serum repletion stay arrested in the G
1
/G
0
phase of the cell cycle in the presence of 2 μM indirubin-3′-monoxime. At higher drug concentrations (≥ 5 μM) an increase of the cell population in the G
2
/M phase is additionally observed. Cells synchronized in G
2
/M phase by nocodazole remain arrested in the G
2
/M phase after release, in the presence of indirubin-3′-monoxime (≥5 μM). After 24 h treatment with 10 μM indirubin-3′-monoxime a sub-G
2
peak appears, indicative for the onset of apoptotic cell death. Treatment of MCF-7 cells with growth inhibitory concentrations of indirubin-3′-monoxime induces dose-dependent inhibition of the CDK1 activity in the cell. After 24 h treatment, a strong decrease of the CDK1 protein level along with a reduction of cyclin B in complex with CDK1 is observed. Taken together, the results of this study strongly suggest that inhibition of CDK activity in human tumour cells is a major mechanism by which indirubin derivatives exert their potent antitumour efficacy. © 2001 Cancer Research Campaign
http://www.bjcancer.com |
| doi_str_mv | 10.1054/bjoc.2000.1546 |
| format | Article |
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1
/G
0
phase of the cell cycle in the presence of 2 μM indirubin-3′-monoxime. At higher drug concentrations (≥ 5 μM) an increase of the cell population in the G
2
/M phase is additionally observed. Cells synchronized in G
2
/M phase by nocodazole remain arrested in the G
2
/M phase after release, in the presence of indirubin-3′-monoxime (≥5 μM). After 24 h treatment with 10 μM indirubin-3′-monoxime a sub-G
2
peak appears, indicative for the onset of apoptotic cell death. Treatment of MCF-7 cells with growth inhibitory concentrations of indirubin-3′-monoxime induces dose-dependent inhibition of the CDK1 activity in the cell. After 24 h treatment, a strong decrease of the CDK1 protein level along with a reduction of cyclin B in complex with CDK1 is observed. Taken together, the results of this study strongly suggest that inhibition of CDK activity in human tumour cells is a major mechanism by which indirubin derivatives exert their potent antitumour efficacy. © 2001 Cancer Research Campaign
http://www.bjcancer.com</description><identifier>ISSN: 0007-0920</identifier><identifier>ISSN: 1532-1827</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1054/bjoc.2000.1546</identifier><identifier>PMID: 11161389</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Antibiotics, Antineoplastic - metabolism ; Antibiotics, Antineoplastic - pharmacology ; Antineoplastic agents ; Apoptosis - drug effects ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; CDC2 Protein Kinase - antagonists & inhibitors ; CDC2 Protein Kinase - metabolism ; Cell culture ; Cell cycle ; Cell Cycle - drug effects ; Cell Division - drug effects ; Chronic illnesses ; Cyclin B - drug effects ; Cyclin B - metabolism ; cyclin-dependent kinase ; Cyclin-dependent kinases ; Dose-Response Relationship, Drug ; Drug Resistance ; Epidemiology ; General aspects ; Humans ; indirubin ; Indoles - chemistry ; Indoles - metabolism ; Indoles - pharmacology ; Inhibitory Concentration 50 ; Kinases ; Leukemia ; Macromolecular Substances ; Medical research ; Medical sciences ; Molecular Medicine ; Oncology ; Pharmacology. Drug treatments ; Proteins ; Regular ; regular-article ; Remission (Medicine) ; Tumor Cells, Cultured - cytology ; Tumor Cells, Cultured - drug effects ; Tumor Cells, Cultured - enzymology</subject><ispartof>British journal of cancer, 2001, Vol.84 (2), p.283-289</ispartof><rights>The Author(s) 2001</rights><rights>2001 INIST-CNRS</rights><rights>Copyright 2001 Cancer Research Campaign.</rights><rights>Copyright Nature Publishing Group Jan 2001</rights><rights>Copyright © 2001 Cancer Research Campaign 2001 Cancer Research Campaign</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c566t-2e52215b2f3f288945ea0844ed528d8ff8a882c1aa11f2c1d4aaca0c9fdc09613</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363695/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363695/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,2725,4022,27922,27923,27924,41487,42556,51318,53790,53792</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=910405$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11161389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marko, D</creatorcontrib><creatorcontrib>Schätzle, S</creatorcontrib><creatorcontrib>Friedel, A</creatorcontrib><creatorcontrib>Genzlinger, A</creatorcontrib><creatorcontrib>Zankl, H</creatorcontrib><creatorcontrib>Meijer, L</creatorcontrib><creatorcontrib>Eisenbrand, G</creatorcontrib><title>Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>The bisindole indirubin has been described, more than 30 years ago, as being clinically active in the treatment of human chronic myelocytic leukaemia. However, the underlying mechanism of action has remained unclear. We have reported previously that indirubin and its analogues are potent and selective inhibitors of cyclin-dependent kinases (CDK). In this study, we investigated the influence of indirubin and derivatives on CDK1/cyclin B kinase in human tumour cells at concentrations known to induce growth inhibition. Cells of the mammary carcinoma cell line MCF-7, synchronized by serum deprivation, after serum repletion stay arrested in the G
1
/G
0
phase of the cell cycle in the presence of 2 μM indirubin-3′-monoxime. At higher drug concentrations (≥ 5 μM) an increase of the cell population in the G
2
/M phase is additionally observed. Cells synchronized in G
2
/M phase by nocodazole remain arrested in the G
2
/M phase after release, in the presence of indirubin-3′-monoxime (≥5 μM). After 24 h treatment with 10 μM indirubin-3′-monoxime a sub-G
2
peak appears, indicative for the onset of apoptotic cell death. Treatment of MCF-7 cells with growth inhibitory concentrations of indirubin-3′-monoxime induces dose-dependent inhibition of the CDK1 activity in the cell. After 24 h treatment, a strong decrease of the CDK1 protein level along with a reduction of cyclin B in complex with CDK1 is observed. Taken together, the results of this study strongly suggest that inhibition of CDK activity in human tumour cells is a major mechanism by which indirubin derivatives exert their potent antitumour efficacy. © 2001 Cancer Research Campaign
http://www.bjcancer.com</description><subject>Antibiotics, Antineoplastic - metabolism</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>CDC2 Protein Kinase - antagonists & inhibitors</subject><subject>CDC2 Protein Kinase - metabolism</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Chronic illnesses</subject><subject>Cyclin B - drug effects</subject><subject>Cyclin B - metabolism</subject><subject>cyclin-dependent kinase</subject><subject>Cyclin-dependent kinases</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance</subject><subject>Epidemiology</subject><subject>General aspects</subject><subject>Humans</subject><subject>indirubin</subject><subject>Indoles - chemistry</subject><subject>Indoles - metabolism</subject><subject>Indoles - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Macromolecular Substances</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Molecular Medicine</subject><subject>Oncology</subject><subject>Pharmacology. Drug treatments</subject><subject>Proteins</subject><subject>Regular</subject><subject>regular-article</subject><subject>Remission (Medicine)</subject><subject>Tumor Cells, Cultured - cytology</subject><subject>Tumor Cells, Cultured - drug effects</subject><subject>Tumor Cells, Cultured - enzymology</subject><issn>0007-0920</issn><issn>1532-1827</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU2P0zAQhi0EYsvClRvIAomPQ7q2Yyf2BQmVrxUrcYEjsiaOvXVJnK6dVOq_x6FVF5DgNBrPM-N35kXoMSVLSgS_aDaDWTJCcip4dQctqChZQSWr76JFfq4Lohg5Qw9S2uRUEVnfR2eU0oqWUi3Q98uw9o0f_RDw4LDZm86HorVbG1obRvzDB0gWU_xq9e4zfY2bPfah9XFqfMCtjX4Ho9_ZlF_xeuoh4HHqhyliY7suPUT3HHTJPjrGc_Ttw_uvq0_F1ZePl6u3V4URVTUWzArGqGiYKx2TUnFhgUjObSuYbKVzEqRkhgJQ6nJsOYABYpRrDVF5k3P05jB3OzW9bU1WHqHT2-h7iHs9gNd_VoJf6-thp1lZlZUSecDL44A43Ew2jbr3aV4Bgh2mpJXgouaKy0y--C9Ja8kI5bOmZ3-Bm3yXkM-gGVNKqlqWGVoeIBOHlKJ1J82U6NlgPRusZ4P1bHBuePr7prf40dEMPD8CkAx0LkIwPp04RQkn874XByrlQri28VbcPz9-cugIME7RngZWlfpV_wmI28dz</recordid><startdate>2001</startdate><enddate>2001</enddate><creator>Marko, D</creator><creator>Schätzle, S</creator><creator>Friedel, A</creator><creator>Genzlinger, A</creator><creator>Zankl, H</creator><creator>Meijer, L</creator><creator>Eisenbrand, G</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7U1</scope><scope>7U2</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>2001</creationdate><title>Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells</title><author>Marko, D ; Schätzle, S ; Friedel, A ; Genzlinger, A ; Zankl, H ; Meijer, L ; Eisenbrand, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c566t-2e52215b2f3f288945ea0844ed528d8ff8a882c1aa11f2c1d4aaca0c9fdc09613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Antibiotics, Antineoplastic - metabolism</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>CDC2 Protein Kinase - antagonists & inhibitors</topic><topic>CDC2 Protein Kinase - metabolism</topic><topic>Cell culture</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Chronic illnesses</topic><topic>Cyclin B - drug effects</topic><topic>Cyclin B - metabolism</topic><topic>cyclin-dependent kinase</topic><topic>Cyclin-dependent kinases</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance</topic><topic>Epidemiology</topic><topic>General aspects</topic><topic>Humans</topic><topic>indirubin</topic><topic>Indoles - chemistry</topic><topic>Indoles - metabolism</topic><topic>Indoles - pharmacology</topic><topic>Inhibitory Concentration 50</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Macromolecular Substances</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Molecular Medicine</topic><topic>Oncology</topic><topic>Pharmacology. Drug treatments</topic><topic>Proteins</topic><topic>Regular</topic><topic>regular-article</topic><topic>Remission (Medicine)</topic><topic>Tumor Cells, Cultured - cytology</topic><topic>Tumor Cells, Cultured - drug effects</topic><topic>Tumor Cells, Cultured - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marko, D</creatorcontrib><creatorcontrib>Schätzle, S</creatorcontrib><creatorcontrib>Friedel, A</creatorcontrib><creatorcontrib>Genzlinger, A</creatorcontrib><creatorcontrib>Zankl, H</creatorcontrib><creatorcontrib>Meijer, L</creatorcontrib><creatorcontrib>Eisenbrand, G</creatorcontrib><collection>Springer Nature OA Free Journals</collection><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>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Risk Abstracts</collection><collection>Safety Science and Risk</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marko, D</au><au>Schätzle, S</au><au>Friedel, A</au><au>Genzlinger, A</au><au>Zankl, H</au><au>Meijer, L</au><au>Eisenbrand, G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2001</date><risdate>2001</risdate><volume>84</volume><issue>2</issue><spage>283</spage><epage>289</epage><pages>283-289</pages><issn>0007-0920</issn><issn>1532-1827</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>The bisindole indirubin has been described, more than 30 years ago, as being clinically active in the treatment of human chronic myelocytic leukaemia. However, the underlying mechanism of action has remained unclear. We have reported previously that indirubin and its analogues are potent and selective inhibitors of cyclin-dependent kinases (CDK). In this study, we investigated the influence of indirubin and derivatives on CDK1/cyclin B kinase in human tumour cells at concentrations known to induce growth inhibition. Cells of the mammary carcinoma cell line MCF-7, synchronized by serum deprivation, after serum repletion stay arrested in the G
1
/G
0
phase of the cell cycle in the presence of 2 μM indirubin-3′-monoxime. At higher drug concentrations (≥ 5 μM) an increase of the cell population in the G
2
/M phase is additionally observed. Cells synchronized in G
2
/M phase by nocodazole remain arrested in the G
2
/M phase after release, in the presence of indirubin-3′-monoxime (≥5 μM). After 24 h treatment with 10 μM indirubin-3′-monoxime a sub-G
2
peak appears, indicative for the onset of apoptotic cell death. Treatment of MCF-7 cells with growth inhibitory concentrations of indirubin-3′-monoxime induces dose-dependent inhibition of the CDK1 activity in the cell. After 24 h treatment, a strong decrease of the CDK1 protein level along with a reduction of cyclin B in complex with CDK1 is observed. Taken together, the results of this study strongly suggest that inhibition of CDK activity in human tumour cells is a major mechanism by which indirubin derivatives exert their potent antitumour efficacy. © 2001 Cancer Research Campaign
http://www.bjcancer.com</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>11161389</pmid><doi>10.1054/bjoc.2000.1546</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of cancer, 2001, Vol.84 (2), p.283-289 |
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| subjects | Antibiotics, Antineoplastic - metabolism Antibiotics, Antineoplastic - pharmacology Antineoplastic agents Apoptosis - drug effects Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research CDC2 Protein Kinase - antagonists & inhibitors CDC2 Protein Kinase - metabolism Cell culture Cell cycle Cell Cycle - drug effects Cell Division - drug effects Chronic illnesses Cyclin B - drug effects Cyclin B - metabolism cyclin-dependent kinase Cyclin-dependent kinases Dose-Response Relationship, Drug Drug Resistance Epidemiology General aspects Humans indirubin Indoles - chemistry Indoles - metabolism Indoles - pharmacology Inhibitory Concentration 50 Kinases Leukemia Macromolecular Substances Medical research Medical sciences Molecular Medicine Oncology Pharmacology. Drug treatments Proteins Regular regular-article Remission (Medicine) Tumor Cells, Cultured - cytology Tumor Cells, Cultured - drug effects Tumor Cells, Cultured - enzymology |
| title | Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells |
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