Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines
[Display omitted] Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its cl...
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| Veröffentlicht in: | Biochemical pharmacology 2018-09, Vol.155, p.316-325 |
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| creator | Wu, Chung-Pu Hsieh, Ya-Ju Murakami, Megumi Vahedi, Shahrooz Hsiao, Sung-Han Yeh, Ni Chou, An-Wei Li, Yan-Qing Wu, Yu-Shan Yu, Jau-Song Ambudkar, Suresh V. |
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Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic. |
| doi_str_mv | 10.1016/j.bcp.2018.07.018 |
| format | Article |
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Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2018.07.018</identifier><identifier>PMID: 30028995</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>ABCB1 ; ABCG2 ; Antineoplastic Agents - pharmacology ; ATP Binding Cassette Transporter, Subfamily B - biosynthesis ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - biosynthesis ; Cell Survival - drug effects ; Cell Survival - physiology ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - physiology ; HDAC6 ; HEK293 Cells ; Histone Deacetylase 6 - antagonists & inhibitors ; Histone Deacetylase 6 - metabolism ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Hydroxamic Acids - pharmacology ; MCF-7 Cells ; Multidrug resistance ; Neoplasm Proteins - biosynthesis ; Pyrimidines - pharmacology ; Ricolinostat</subject><ispartof>Biochemical pharmacology, 2018-09, Vol.155, p.316-325</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-9ea5cd89e72b2c78f7520330e26b2c3ca031881825b4efb417aba1dcef6212b93</citedby><cites>FETCH-LOGICAL-c517t-9ea5cd89e72b2c78f7520330e26b2c3ca031881825b4efb417aba1dcef6212b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bcp.2018.07.018$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30028995$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Chung-Pu</creatorcontrib><creatorcontrib>Hsieh, Ya-Ju</creatorcontrib><creatorcontrib>Murakami, Megumi</creatorcontrib><creatorcontrib>Vahedi, Shahrooz</creatorcontrib><creatorcontrib>Hsiao, Sung-Han</creatorcontrib><creatorcontrib>Yeh, Ni</creatorcontrib><creatorcontrib>Chou, An-Wei</creatorcontrib><creatorcontrib>Li, Yan-Qing</creatorcontrib><creatorcontrib>Wu, Yu-Shan</creatorcontrib><creatorcontrib>Yu, Jau-Song</creatorcontrib><creatorcontrib>Ambudkar, Suresh V.</creatorcontrib><title>Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>[Display omitted]
Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic.</description><subject>ABCB1</subject><subject>ABCG2</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>ATP Binding Cassette Transporter, Subfamily B - biosynthesis</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2 - biosynthesis</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - physiology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>HDAC6</subject><subject>HEK293 Cells</subject><subject>Histone Deacetylase 6 - antagonists & inhibitors</subject><subject>Histone Deacetylase 6 - metabolism</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>MCF-7 Cells</subject><subject>Multidrug resistance</subject><subject>Neoplasm Proteins - biosynthesis</subject><subject>Pyrimidines - pharmacology</subject><subject>Ricolinostat</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcFq3DAQFaWl2ab9gF6Kju3BrkaOLZlCYbO0SSCQHNJDT0KWx1ktXmmRlEA-JX_bWbYNzSWnN8O894aZx9hHEDUI6L5u6sHtailA10LVBK_YArRqKtl3-jVbCCE6qlt5xN7lvNm3uoO37KgRQuq-bxfs8fxuawNf3lxXgw-jD7fc2ZyxFOQl2ZB3MRVMmS9PV6fAbRj31ZnkLoYJE0-YfS42OKJHvqY6BuQjWoflYbYZecd9WPvBl0hs7-LsQyRF4Z-Xq98VSGi_EIO2kkfiDueZEwXze_ZmsnPGD3_xmP36-eNmdV5dXp1drJaXlWtBlapH27pR96jkIJ3Sk2qlaBqBsqO-cVY0oDVo2Q4nOA0noOxgYXQ4dRLk0DfH7PvBd3c3bJEGge6ezS75rU0PJlpvnk-CX5vbeG9UrxtQggzgYOBSzDnh9KQFYfY5mY2hnMw-JyOUISDNp_-XPin-BUOEbwcC0un3HpPJziO9aPQJXTFj9C_Y_wHut6VD</recordid><startdate>20180901</startdate><enddate>20180901</enddate><creator>Wu, Chung-Pu</creator><creator>Hsieh, Ya-Ju</creator><creator>Murakami, Megumi</creator><creator>Vahedi, Shahrooz</creator><creator>Hsiao, Sung-Han</creator><creator>Yeh, Ni</creator><creator>Chou, An-Wei</creator><creator>Li, Yan-Qing</creator><creator>Wu, Yu-Shan</creator><creator>Yu, Jau-Song</creator><creator>Ambudkar, Suresh V.</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>20180901</creationdate><title>Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines</title><author>Wu, Chung-Pu ; Hsieh, Ya-Ju ; Murakami, Megumi ; Vahedi, Shahrooz ; Hsiao, Sung-Han ; Yeh, Ni ; Chou, An-Wei ; Li, Yan-Qing ; Wu, Yu-Shan ; Yu, Jau-Song ; Ambudkar, Suresh V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c517t-9ea5cd89e72b2c78f7520330e26b2c3ca031881825b4efb417aba1dcef6212b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>ABCB1</topic><topic>ABCG2</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>ATP Binding Cassette Transporter, Subfamily B - biosynthesis</topic><topic>ATP Binding Cassette Transporter, Subfamily G, Member 2 - biosynthesis</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - physiology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>HDAC6</topic><topic>HEK293 Cells</topic><topic>Histone Deacetylase 6 - antagonists & inhibitors</topic><topic>Histone Deacetylase 6 - metabolism</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>MCF-7 Cells</topic><topic>Multidrug resistance</topic><topic>Neoplasm Proteins - biosynthesis</topic><topic>Pyrimidines - pharmacology</topic><topic>Ricolinostat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Chung-Pu</creatorcontrib><creatorcontrib>Hsieh, Ya-Ju</creatorcontrib><creatorcontrib>Murakami, Megumi</creatorcontrib><creatorcontrib>Vahedi, Shahrooz</creatorcontrib><creatorcontrib>Hsiao, Sung-Han</creatorcontrib><creatorcontrib>Yeh, Ni</creatorcontrib><creatorcontrib>Chou, An-Wei</creatorcontrib><creatorcontrib>Li, Yan-Qing</creatorcontrib><creatorcontrib>Wu, Yu-Shan</creatorcontrib><creatorcontrib>Yu, Jau-Song</creatorcontrib><creatorcontrib>Ambudkar, Suresh V.</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>Wu, Chung-Pu</au><au>Hsieh, Ya-Ju</au><au>Murakami, Megumi</au><au>Vahedi, Shahrooz</au><au>Hsiao, Sung-Han</au><au>Yeh, Ni</au><au>Chou, An-Wei</au><au>Li, Yan-Qing</au><au>Wu, Yu-Shan</au><au>Yu, Jau-Song</au><au>Ambudkar, Suresh V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2018-09-01</date><risdate>2018</risdate><volume>155</volume><spage>316</spage><epage>325</epage><pages>316-325</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>[Display omitted]
Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>30028995</pmid><doi>10.1016/j.bcp.2018.07.018</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Biochemical pharmacology, 2018-09, Vol.155, p.316-325 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | ABCB1 ABCG2 Antineoplastic Agents - pharmacology ATP Binding Cassette Transporter, Subfamily B - biosynthesis ATP Binding Cassette Transporter, Subfamily G, Member 2 - biosynthesis Cell Survival - drug effects Cell Survival - physiology Dose-Response Relationship, Drug Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - physiology HDAC6 HEK293 Cells Histone Deacetylase 6 - antagonists & inhibitors Histone Deacetylase 6 - metabolism Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - pharmacology MCF-7 Cells Multidrug resistance Neoplasm Proteins - biosynthesis Pyrimidines - pharmacology Ricolinostat |
| title | Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines |
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