Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules
Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase...
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| Veröffentlicht in: | Cancer cell 2015-07, Vol.28 (1), p.82-96 |
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| creator | Yu, Yu Gaillard, Stephanie Phillip, Jude M. Huang, Tai-Chung Pinto, Sneha M. Tessarollo, Nayara G. Zhang, Zhen Pandey, Akhilesh Wirtz, Denis Ayhan, Ayse Davidson, Ben Wang, Tian-Li Shih, Ie-Ming |
| description | Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
[Display omitted]
•SYK is overexpressed in recurrent post-chemotherapy ovarian cancers•Inhibition of SYK synergistically enhances sensitivity to paclitaxel in tumor cells•SYK inhibition stabilizes microtubule in the presence of paclitaxel•Tubulin and MAPs are SYK substrates that may contribute to paclitaxel resistance
Yu et al. show that ovarian cancer cells surviving paclitaxel treatment have higher levels of activated spleen tyrosine kinase (SYK). Importantly, inhibition of SYK sensitizes ovarian cancer cells to paclitaxel treatment via enhancing microtubule stability. |
| doi_str_mv | 10.1016/j.ccell.2015.05.009 |
| format | Article |
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[Display omitted]
•SYK is overexpressed in recurrent post-chemotherapy ovarian cancers•Inhibition of SYK synergistically enhances sensitivity to paclitaxel in tumor cells•SYK inhibition stabilizes microtubule in the presence of paclitaxel•Tubulin and MAPs are SYK substrates that may contribute to paclitaxel resistance
Yu et al. show that ovarian cancer cells surviving paclitaxel treatment have higher levels of activated spleen tyrosine kinase (SYK). Importantly, inhibition of SYK sensitizes ovarian cancer cells to paclitaxel treatment via enhancing microtubule stability.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2015.05.009</identifier><identifier>PMID: 26096845</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cell Line, Tumor ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Female ; Gene Knockdown Techniques ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Microtubule-Associated Proteins - metabolism ; Microtubules - drug effects ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Oxazines - administration & dosage ; Oxazines - pharmacology ; Paclitaxel - administration & dosage ; Paclitaxel - pharmacology ; Phosphorylation - drug effects ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; Pyridines - administration & dosage ; Pyridines - pharmacology ; Syk Kinase ; Tubulin - metabolism ; Up-Regulation ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer cell, 2015-07, Vol.28 (1), p.82-96</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c628t-b1d549a9367c056e8f890cd34d3149665d072c4ecd817b5a80be464631aa63d83</citedby><cites>FETCH-LOGICAL-c628t-b1d549a9367c056e8f890cd34d3149665d072c4ecd817b5a80be464631aa63d83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610815001853$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26096845$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Yu</creatorcontrib><creatorcontrib>Gaillard, Stephanie</creatorcontrib><creatorcontrib>Phillip, Jude M.</creatorcontrib><creatorcontrib>Huang, Tai-Chung</creatorcontrib><creatorcontrib>Pinto, Sneha M.</creatorcontrib><creatorcontrib>Tessarollo, Nayara G.</creatorcontrib><creatorcontrib>Zhang, Zhen</creatorcontrib><creatorcontrib>Pandey, Akhilesh</creatorcontrib><creatorcontrib>Wirtz, Denis</creatorcontrib><creatorcontrib>Ayhan, Ayse</creatorcontrib><creatorcontrib>Davidson, Ben</creatorcontrib><creatorcontrib>Wang, Tian-Li</creatorcontrib><creatorcontrib>Shih, Ie-Ming</creatorcontrib><title>Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
[Display omitted]
•SYK is overexpressed in recurrent post-chemotherapy ovarian cancers•Inhibition of SYK synergistically enhances sensitivity to paclitaxel in tumor cells•SYK inhibition stabilizes microtubule in the presence of paclitaxel•Tubulin and MAPs are SYK substrates that may contribute to paclitaxel resistance
Yu et al. show that ovarian cancer cells surviving paclitaxel treatment have higher levels of activated spleen tyrosine kinase (SYK). Importantly, inhibition of SYK sensitizes ovarian cancer cells to paclitaxel treatment via enhancing microtubule stability.</description><subject>Cell Line, Tumor</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Microtubules - drug effects</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Oxazines - administration & dosage</subject><subject>Oxazines - pharmacology</subject><subject>Paclitaxel - administration & dosage</subject><subject>Paclitaxel - pharmacology</subject><subject>Phosphorylation - drug effects</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Pyridines - administration & dosage</subject><subject>Pyridines - pharmacology</subject><subject>Syk Kinase</subject><subject>Tubulin - metabolism</subject><subject>Up-Regulation</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhiMEoh_wC5CQj1yy2EnsOAeQUFRgRVErtZwtx55tZ5W1F9tZNZz54fWypYILSCPZ0rwz8848RfGK0QWjTLxdL4yBcVxUlPEFzUG7J8Uxk60sayHF0_znNS8Fo_KoOIlxTXMVa7vnxVElaCdkw4-Ln0t3iwMm9I74FbnajgCOXM_BR3RAvqDTEcilT-AS6gSRXGozYtJ3MJZLZycDlvRz8snfocE0E3TkYqcDakd67QwE0meXkQwzuUp6wBF_oLshX9EEn6ZhGiG-KJ6t9Bjh5cN7Wnz7eHbdfy7PLz4t-w_npRGVTOXALG863dWiNZQLkCvZUWPrxtas6YTglraVacBYydqBa0kHaEQjaqa1qK2sT4v3h77badiANXmnoEe1DbjRYVZeo_o74_BW3fid4hVvq7bLDd48NAj--wQxqQ3GPQTtwE9RsZaziuaZ7P9SkQlIIesmS-uDNF8kxgCrR0eMqj1qtVa_UKs9akVz0L2X138u81jzm20WvDsIIJ90hxBUNAiZiMUAJinr8Z8D7gFmsL5N</recordid><startdate>20150713</startdate><enddate>20150713</enddate><creator>Yu, Yu</creator><creator>Gaillard, Stephanie</creator><creator>Phillip, Jude M.</creator><creator>Huang, Tai-Chung</creator><creator>Pinto, Sneha M.</creator><creator>Tessarollo, Nayara G.</creator><creator>Zhang, Zhen</creator><creator>Pandey, Akhilesh</creator><creator>Wirtz, Denis</creator><creator>Ayhan, Ayse</creator><creator>Davidson, Ben</creator><creator>Wang, Tian-Li</creator><creator>Shih, Ie-Ming</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150713</creationdate><title>Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules</title><author>Yu, Yu ; Gaillard, Stephanie ; Phillip, Jude M. ; Huang, Tai-Chung ; Pinto, Sneha M. ; Tessarollo, Nayara G. ; Zhang, Zhen ; Pandey, Akhilesh ; Wirtz, Denis ; Ayhan, Ayse ; Davidson, Ben ; Wang, Tian-Li ; Shih, Ie-Ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c628t-b1d549a9367c056e8f890cd34d3149665d072c4ecd817b5a80be464631aa63d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Cell Line, Tumor</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Microtubules - drug effects</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Oxazines - administration & dosage</topic><topic>Oxazines - pharmacology</topic><topic>Paclitaxel - administration & dosage</topic><topic>Paclitaxel - pharmacology</topic><topic>Phosphorylation - drug effects</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - genetics</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Pyridines - administration & dosage</topic><topic>Pyridines - pharmacology</topic><topic>Syk Kinase</topic><topic>Tubulin - metabolism</topic><topic>Up-Regulation</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Yu</creatorcontrib><creatorcontrib>Gaillard, Stephanie</creatorcontrib><creatorcontrib>Phillip, Jude M.</creatorcontrib><creatorcontrib>Huang, Tai-Chung</creatorcontrib><creatorcontrib>Pinto, Sneha M.</creatorcontrib><creatorcontrib>Tessarollo, Nayara G.</creatorcontrib><creatorcontrib>Zhang, Zhen</creatorcontrib><creatorcontrib>Pandey, Akhilesh</creatorcontrib><creatorcontrib>Wirtz, Denis</creatorcontrib><creatorcontrib>Ayhan, Ayse</creatorcontrib><creatorcontrib>Davidson, Ben</creatorcontrib><creatorcontrib>Wang, Tian-Li</creatorcontrib><creatorcontrib>Shih, Ie-Ming</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Yu</au><au>Gaillard, Stephanie</au><au>Phillip, Jude M.</au><au>Huang, Tai-Chung</au><au>Pinto, Sneha M.</au><au>Tessarollo, Nayara G.</au><au>Zhang, Zhen</au><au>Pandey, Akhilesh</au><au>Wirtz, Denis</au><au>Ayhan, Ayse</au><au>Davidson, Ben</au><au>Wang, Tian-Li</au><au>Shih, Ie-Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2015-07-13</date><risdate>2015</risdate><volume>28</volume><issue>1</issue><spage>82</spage><epage>96</epage><pages>82-96</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
[Display omitted]
•SYK is overexpressed in recurrent post-chemotherapy ovarian cancers•Inhibition of SYK synergistically enhances sensitivity to paclitaxel in tumor cells•SYK inhibition stabilizes microtubule in the presence of paclitaxel•Tubulin and MAPs are SYK substrates that may contribute to paclitaxel resistance
Yu et al. show that ovarian cancer cells surviving paclitaxel treatment have higher levels of activated spleen tyrosine kinase (SYK). Importantly, inhibition of SYK sensitizes ovarian cancer cells to paclitaxel treatment via enhancing microtubule stability.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26096845</pmid><doi>10.1016/j.ccell.2015.05.009</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2015-07, Vol.28 (1), p.82-96 |
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| language | eng |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Drug Synergism Female Gene Knockdown Techniques Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Microtubule-Associated Proteins - metabolism Microtubules - drug effects Ovarian Neoplasms - drug therapy Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Oxazines - administration & dosage Oxazines - pharmacology Paclitaxel - administration & dosage Paclitaxel - pharmacology Phosphorylation - drug effects Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Pyridines - administration & dosage Pyridines - pharmacology Syk Kinase Tubulin - metabolism Up-Regulation Xenograft Model Antitumor Assays |
| title | Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules |
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