Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo
[Display omitted] Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report...
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Veröffentlicht in: | Biochemical pharmacology 2014-05, Vol.89 (1), p.52-61 |
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creator | Sodani, Kamlesh Patel, Atish Anreddy, Nagaraju Singh, Satyakam Yang, Dong-Hua Kathawala, Rishil J. Kumar, Priyank Talele, Tanaji T. Chen, Zhe-Sheng |
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Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2. |
doi_str_mv | 10.1016/j.bcp.2014.02.012 |
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Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2014.02.012</identifier><identifier>PMID: 24565910</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>ABC transporter ; ABCG2 ; Animals ; Antineoplastic Agents - therapeutic use ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - physiology ; Drug Resistance, Neoplasm ; Humans ; In Vitro Techniques ; Male ; Mice ; Mice, Nude ; Multidrug resistance ; Neoplasm Proteins - genetics ; Neoplasm Proteins - physiology ; Pyridazines - therapeutic use ; Pyridines - therapeutic use ; Telatinib ; Tyrosine kinase inhibitor</subject><ispartof>Biochemical pharmacology, 2014-05, Vol.89 (1), p.52-61</ispartof><rights>2014 Elsevier Inc.</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><rights>2014 Elsevier Inc. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-3cf218cbb7d5bdc78f78b0cac5b5678bf74c693b72d1a7fe824f6c6c94502ee73</citedby><cites>FETCH-LOGICAL-c451t-3cf218cbb7d5bdc78f78b0cac5b5678bf74c693b72d1a7fe824f6c6c94502ee73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006295214001257$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24565910$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sodani, Kamlesh</creatorcontrib><creatorcontrib>Patel, Atish</creatorcontrib><creatorcontrib>Anreddy, Nagaraju</creatorcontrib><creatorcontrib>Singh, Satyakam</creatorcontrib><creatorcontrib>Yang, Dong-Hua</creatorcontrib><creatorcontrib>Kathawala, Rishil J.</creatorcontrib><creatorcontrib>Kumar, Priyank</creatorcontrib><creatorcontrib>Talele, Tanaji T.</creatorcontrib><creatorcontrib>Chen, Zhe-Sheng</creatorcontrib><title>Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>[Display omitted]
Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.</description><subject>ABC transporter</subject><subject>ABCG2</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>ATP Binding Cassette Transporter, Sub-Family G, Member 2</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - physiology</subject><subject>Drug Resistance, Neoplasm</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Multidrug resistance</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - physiology</subject><subject>Pyridazines - therapeutic use</subject><subject>Pyridines - therapeutic use</subject><subject>Telatinib</subject><subject>Tyrosine kinase inhibitor</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQtRCILm1_ABfkP7DBdhI7ERJSWUGLVIlLOVv2eNz1KptEthPRf49XCxVcepoZzXtvPh4h7zmrOOPy46GyMFeC8aZiomJcvCIb3ql6K3rZvSYbxpgseSsuyLuUDqeyk_wtuRBNK9uesw2JDziYHMZgacQVY8JEYY_HKe8xmhmXHIAelyEHF5fHgkkhZTMC0iO6YDI6ap_ozZfdraDo_bD8ojmaMc1TzBhpGOkacpyoGd25WKcr8sabIeH1n3hJfn77-rC7297_uP2-u7nfQtPyvK3BC96Btcq11oHqvOosAwOtbWVJvWpA9rVVwnGjPHai8RIk9E3LBKKqL8nns-682LIs4Fg2G_Qcw9HEJz2ZoP_vjGGvH6dV131XK86LAD8LQJxSiuifuZzpkwH6oIsB-mSAZkIXAwrnw79Dnxl_P14An84ALKevAaNOELA81IWIkLWbwgvyvwEypprK</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Sodani, Kamlesh</creator><creator>Patel, Atish</creator><creator>Anreddy, Nagaraju</creator><creator>Singh, Satyakam</creator><creator>Yang, Dong-Hua</creator><creator>Kathawala, Rishil J.</creator><creator>Kumar, Priyank</creator><creator>Talele, Tanaji T.</creator><creator>Chen, Zhe-Sheng</creator><general>Elsevier Inc</general><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>5PM</scope></search><sort><creationdate>20140501</creationdate><title>Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo</title><author>Sodani, Kamlesh ; Patel, Atish ; Anreddy, Nagaraju ; Singh, Satyakam ; Yang, Dong-Hua ; Kathawala, Rishil J. ; Kumar, Priyank ; Talele, Tanaji T. ; Chen, Zhe-Sheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-3cf218cbb7d5bdc78f78b0cac5b5678bf74c693b72d1a7fe824f6c6c94502ee73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>ABC transporter</topic><topic>ABCG2</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>ATP Binding Cassette Transporter, Sub-Family G, Member 2</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - physiology</topic><topic>Drug Resistance, Neoplasm</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Multidrug resistance</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - physiology</topic><topic>Pyridazines - therapeutic use</topic><topic>Pyridines - therapeutic use</topic><topic>Telatinib</topic><topic>Tyrosine kinase inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sodani, Kamlesh</creatorcontrib><creatorcontrib>Patel, Atish</creatorcontrib><creatorcontrib>Anreddy, Nagaraju</creatorcontrib><creatorcontrib>Singh, Satyakam</creatorcontrib><creatorcontrib>Yang, Dong-Hua</creatorcontrib><creatorcontrib>Kathawala, Rishil J.</creatorcontrib><creatorcontrib>Kumar, Priyank</creatorcontrib><creatorcontrib>Talele, Tanaji T.</creatorcontrib><creatorcontrib>Chen, Zhe-Sheng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sodani, Kamlesh</au><au>Patel, Atish</au><au>Anreddy, Nagaraju</au><au>Singh, Satyakam</au><au>Yang, Dong-Hua</au><au>Kathawala, Rishil J.</au><au>Kumar, Priyank</au><au>Talele, Tanaji T.</au><au>Chen, Zhe-Sheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>89</volume><issue>1</issue><spage>52</spage><epage>61</epage><pages>52-61</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>[Display omitted]
Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>24565910</pmid><doi>10.1016/j.bcp.2014.02.012</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | ABC transporter ABCG2 Animals Antineoplastic Agents - therapeutic use ATP Binding Cassette Transporter, Sub-Family G, Member 2 ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - physiology Drug Resistance, Neoplasm Humans In Vitro Techniques Male Mice Mice, Nude Multidrug resistance Neoplasm Proteins - genetics Neoplasm Proteins - physiology Pyridazines - therapeutic use Pyridines - therapeutic use Telatinib Tyrosine kinase inhibitor |
title | Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo |
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