DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells
To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabi...
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| Veröffentlicht in: | Experimental oncology 2010-12, Vol.32 (4), p.258-262 |
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| creator | Svirnovski, A I Serhiyenka, T F Kustanovich, A M Khlebko, P V Fedosenko, V V Taras, I B Bakun, A V |
| description | To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients.
Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated.
Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS.
Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL. |
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Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated.
Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS.
Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL.</description><identifier>ISSN: 1812-9269</identifier><identifier>PMID: 21270755</identifier><language>eng</language><publisher>Ukraine</publisher><subject><![CDATA[Antineoplastic Agents - pharmacology ; Ataxia Telangiectasia Mutated Proteins ; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors ; Benzaldehydes - pharmacology ; Blotting, Western ; Caffeine - pharmacology ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Line, Tumor ; Chromones - pharmacology ; Cyclosporine - pharmacology ; DNA-Activated Protein Kinase - antagonists & inhibitors ; DNA-Binding Proteins - antagonists & inhibitors ; Drug Resistance, Neoplasm - drug effects ; Flow Cytometry ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Morpholines - pharmacology ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Tumor Suppressor Proteins - antagonists & inhibitors ; Vidarabine - analogs & derivatives ; Vidarabine - pharmacology]]></subject><ispartof>Experimental oncology, 2010-12, Vol.32 (4), p.258-262</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21270755$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Svirnovski, A I</creatorcontrib><creatorcontrib>Serhiyenka, T F</creatorcontrib><creatorcontrib>Kustanovich, A M</creatorcontrib><creatorcontrib>Khlebko, P V</creatorcontrib><creatorcontrib>Fedosenko, V V</creatorcontrib><creatorcontrib>Taras, I B</creatorcontrib><creatorcontrib>Bakun, A V</creatorcontrib><title>DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells</title><title>Experimental oncology</title><addtitle>Exp Oncol</addtitle><description>To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients.
Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated.
Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS.
Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors</subject><subject>Benzaldehydes - pharmacology</subject><subject>Blotting, Western</subject><subject>Caffeine - pharmacology</subject><subject>Cell Cycle Proteins - antagonists & inhibitors</subject><subject>Cell Line, Tumor</subject><subject>Chromones - pharmacology</subject><subject>Cyclosporine - pharmacology</subject><subject>DNA-Activated Protein Kinase - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Morpholines - pharmacology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Tumor Suppressor Proteins - antagonists & inhibitors</subject><subject>Vidarabine - analogs & derivatives</subject><subject>Vidarabine - pharmacology</subject><issn>1812-9269</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kDtPwzAcxD2AaCl8BeSNhUh-xI-MUcpLpIBQGZgix_kXjBKn2AkS355ElOXuhp9OpztCS6opSzImswU6jfGTECkymZ6gBaNMESXEEr2tH_Pk-eEK59sNNr7Bm_UL3od-AOcjdv7D1W7owxxx_w3B9p3z73jXjo0JpnYecIDo4mC8hRkqyhJbaNt4ho53po1wfvAVer253hZ3Sfl0e1_kZbKnTAxJoxXjhBhgTcZYaiyfhEvFZwcqCYDJUsua2limGedKakWtkkIRkqacr9DlX--0-muEOFSdi_MC46EfY6VTzamgUk7kxYEc6w6aah9cZ8JP9f8G_wWk1lgH</recordid><startdate>201012</startdate><enddate>201012</enddate><creator>Svirnovski, A I</creator><creator>Serhiyenka, T F</creator><creator>Kustanovich, A M</creator><creator>Khlebko, P V</creator><creator>Fedosenko, V V</creator><creator>Taras, I B</creator><creator>Bakun, A V</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201012</creationdate><title>DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells</title><author>Svirnovski, A I ; Serhiyenka, T F ; Kustanovich, A M ; Khlebko, P V ; Fedosenko, V V ; Taras, I B ; Bakun, A V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p125t-d872300ae2d9224ac324a3673324ae160eea94c2dbac2823376871c7657004433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors</topic><topic>Benzaldehydes - pharmacology</topic><topic>Blotting, Western</topic><topic>Caffeine - pharmacology</topic><topic>Cell Cycle Proteins - antagonists & inhibitors</topic><topic>Cell Line, Tumor</topic><topic>Chromones - pharmacology</topic><topic>Cyclosporine - pharmacology</topic><topic>DNA-Activated Protein Kinase - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Morpholines - pharmacology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Tumor Suppressor Proteins - antagonists & inhibitors</topic><topic>Vidarabine - analogs & derivatives</topic><topic>Vidarabine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Svirnovski, A I</creatorcontrib><creatorcontrib>Serhiyenka, T F</creatorcontrib><creatorcontrib>Kustanovich, A M</creatorcontrib><creatorcontrib>Khlebko, P V</creatorcontrib><creatorcontrib>Fedosenko, V V</creatorcontrib><creatorcontrib>Taras, I B</creatorcontrib><creatorcontrib>Bakun, A V</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>Experimental oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Svirnovski, A I</au><au>Serhiyenka, T F</au><au>Kustanovich, A M</au><au>Khlebko, P V</au><au>Fedosenko, V V</au><au>Taras, I B</au><au>Bakun, A V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells</atitle><jtitle>Experimental oncology</jtitle><addtitle>Exp Oncol</addtitle><date>2010-12</date><risdate>2010</risdate><volume>32</volume><issue>4</issue><spage>258</spage><epage>262</epage><pages>258-262</pages><issn>1812-9269</issn><abstract>To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients.
Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated.
Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS.
Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL.</abstract><cop>Ukraine</cop><pmid>21270755</pmid><tpages>5</tpages></addata></record> |
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| subjects | Antineoplastic Agents - pharmacology Ataxia Telangiectasia Mutated Proteins ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors Benzaldehydes - pharmacology Blotting, Western Caffeine - pharmacology Cell Cycle Proteins - antagonists & inhibitors Cell Line, Tumor Chromones - pharmacology Cyclosporine - pharmacology DNA-Activated Protein Kinase - antagonists & inhibitors DNA-Binding Proteins - antagonists & inhibitors Drug Resistance, Neoplasm - drug effects Flow Cytometry Humans Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Morpholines - pharmacology Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Tumor Suppressor Proteins - antagonists & inhibitors Vidarabine - analogs & derivatives Vidarabine - pharmacology |
| title | DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells |
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