Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells
An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients wit...
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| Veröffentlicht in: | Scientific reports 2019-04, Vol.9 (1), p.5759, Article 5759 |
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| creator | Hayasaka, Naotaka Takada, Kohichi Nakamura, Hajime Arihara, Yohei Kawano, Yutaka Osuga, Takahiro Murase, Kazuyuki Kikuchi, Shohei Iyama, Satoshi Emori, Makoto Sugita, Shintaro Hasegawa, Tadashi Takasawa, Akira Miyanishi, Koji Kobune, Masayoshi Kato, Junji |
| description | An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth
in vivo
as well as
in vitro
. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS. |
| doi_str_mv | 10.1038/s41598-019-42300-z |
| format | Article |
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in vivo
as well as
in vitro
. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-42300-z</identifier><identifier>PMID: 30962488</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/2 ; 13/31 ; 64/60 ; 692/4028/67/1798 ; 692/699/67/1798 ; 82/80 ; AKT protein ; Animals ; Antineoplastic Agents - toxicity ; Apoptosis ; Apoptosis - drug effects ; Breast cancer ; Caspase ; Cdc2 protein ; Cell Cycle Checkpoints ; Cell Line ; Cell Line, Tumor ; Cyclin-dependent kinases ; Cyclin-Dependent Kinases - genetics ; Cyclin-Dependent Kinases - metabolism ; Cyclins ; Cyclins - genetics ; Cyclins - metabolism ; Cytotoxicity ; Drug Synergism ; Furans - toxicity ; Heterocyclic Compounds, 3-Ring - toxicity ; Humanities and Social Sciences ; Humans ; Ketones - toxicity ; Liposarcoma ; Metastases ; Mice ; Mice, Inbred BALB C ; multidisciplinary ; Protein Kinase Inhibitors - toxicity ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Sarcoma ; Sarcoma - metabolism ; Science ; Science (multidisciplinary) ; Soft Tissue Neoplasms - metabolism ; Soft tissue sarcoma ; Tissues ; Tumors</subject><ispartof>Scientific reports, 2019-04, Vol.9 (1), p.5759, Article 5759</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-4a0008498b5dbfb0cee19b8134e8cecaf2f2a1fb982a5ce407d7871f9820255d3</citedby><cites>FETCH-LOGICAL-c540t-4a0008498b5dbfb0cee19b8134e8cecaf2f2a1fb982a5ce407d7871f9820255d3</cites><orcidid>0000-0003-3828-8444</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453888/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453888/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30962488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hayasaka, Naotaka</creatorcontrib><creatorcontrib>Takada, Kohichi</creatorcontrib><creatorcontrib>Nakamura, Hajime</creatorcontrib><creatorcontrib>Arihara, Yohei</creatorcontrib><creatorcontrib>Kawano, Yutaka</creatorcontrib><creatorcontrib>Osuga, Takahiro</creatorcontrib><creatorcontrib>Murase, Kazuyuki</creatorcontrib><creatorcontrib>Kikuchi, Shohei</creatorcontrib><creatorcontrib>Iyama, Satoshi</creatorcontrib><creatorcontrib>Emori, Makoto</creatorcontrib><creatorcontrib>Sugita, Shintaro</creatorcontrib><creatorcontrib>Hasegawa, Tadashi</creatorcontrib><creatorcontrib>Takasawa, Akira</creatorcontrib><creatorcontrib>Miyanishi, Koji</creatorcontrib><creatorcontrib>Kobune, Masayoshi</creatorcontrib><creatorcontrib>Kato, Junji</creatorcontrib><title>Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth
in vivo
as well as
in vitro
. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.</description><subject>13/1</subject><subject>13/2</subject><subject>13/31</subject><subject>64/60</subject><subject>692/4028/67/1798</subject><subject>692/699/67/1798</subject><subject>82/80</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Breast cancer</subject><subject>Caspase</subject><subject>Cdc2 protein</subject><subject>Cell Cycle Checkpoints</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cyclin-dependent kinases</subject><subject>Cyclin-Dependent Kinases - genetics</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Cyclins</subject><subject>Cyclins - genetics</subject><subject>Cyclins - metabolism</subject><subject>Cytotoxicity</subject><subject>Drug Synergism</subject><subject>Furans - toxicity</subject><subject>Heterocyclic Compounds, 3-Ring - toxicity</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Ketones - toxicity</subject><subject>Liposarcoma</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>multidisciplinary</subject><subject>Protein Kinase Inhibitors - toxicity</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Sarcoma</subject><subject>Sarcoma - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Soft Tissue Neoplasms - metabolism</subject><subject>Soft tissue sarcoma</subject><subject>Tissues</subject><subject>Tumors</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</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>eNp9kc1OWzEQha2KqiDKC3RRWer6gn8Te4OEIloqkNjQtWU742B6YwfbFzU8fU1DgW46G481Z84c6UPoEyXHlHB1UgWVWg2E6kEwTsjw-A4dMCLkwDhje2_6fXRU6x3pJZkWVH9A-5zoGRNKHaDVIq9dTLbFnHAOGEp00xgT3oxTxWeXNzim2-hiywXDQ_4JFddtgrKKtUWP_bblln9FH9u2K3HNoeEWa50AV1t8XlvsYRzrR_Q-2LHC0fN7iH58Pb9ZXAxX19--L86uBi8FaYOwPaYSWjm5dMERD0C1U5QLUB68DSwwS4PTilnpQZD5cq7mNPQ_YVIu-SE63fluJreGpYfUih3NpsS1LVuTbTT_TlK8Nav8YGZCcqVUN_jybFDy_QS1mbs8ldQzG8aI5FrPZ08qtlP5kmstEF4uUGKe-JgdH9P5mD98zGNf-vw228vKXxpdwHeC2kdpBeX19n9sfwM5IZ8d</recordid><startdate>20190408</startdate><enddate>20190408</enddate><creator>Hayasaka, Naotaka</creator><creator>Takada, Kohichi</creator><creator>Nakamura, Hajime</creator><creator>Arihara, Yohei</creator><creator>Kawano, Yutaka</creator><creator>Osuga, Takahiro</creator><creator>Murase, Kazuyuki</creator><creator>Kikuchi, Shohei</creator><creator>Iyama, Satoshi</creator><creator>Emori, Makoto</creator><creator>Sugita, Shintaro</creator><creator>Hasegawa, Tadashi</creator><creator>Takasawa, Akira</creator><creator>Miyanishi, Koji</creator><creator>Kobune, Masayoshi</creator><creator>Kato, Junji</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</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>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3828-8444</orcidid></search><sort><creationdate>20190408</creationdate><title>Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells</title><author>Hayasaka, Naotaka ; Takada, Kohichi ; Nakamura, Hajime ; Arihara, Yohei ; Kawano, Yutaka ; Osuga, Takahiro ; Murase, Kazuyuki ; Kikuchi, Shohei ; Iyama, Satoshi ; Emori, Makoto ; Sugita, Shintaro ; Hasegawa, Tadashi ; Takasawa, Akira ; Miyanishi, Koji ; Kobune, Masayoshi ; Kato, Junji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-4a0008498b5dbfb0cee19b8134e8cecaf2f2a1fb982a5ce407d7871f9820255d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/1</topic><topic>13/2</topic><topic>13/31</topic><topic>64/60</topic><topic>692/4028/67/1798</topic><topic>692/699/67/1798</topic><topic>82/80</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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metabolism</topic><topic>Sarcoma</topic><topic>Sarcoma - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Soft Tissue Neoplasms - metabolism</topic><topic>Soft tissue sarcoma</topic><topic>Tissues</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hayasaka, Naotaka</creatorcontrib><creatorcontrib>Takada, Kohichi</creatorcontrib><creatorcontrib>Nakamura, Hajime</creatorcontrib><creatorcontrib>Arihara, Yohei</creatorcontrib><creatorcontrib>Kawano, Yutaka</creatorcontrib><creatorcontrib>Osuga, Takahiro</creatorcontrib><creatorcontrib>Murase, Kazuyuki</creatorcontrib><creatorcontrib>Kikuchi, Shohei</creatorcontrib><creatorcontrib>Iyama, Satoshi</creatorcontrib><creatorcontrib>Emori, Makoto</creatorcontrib><creatorcontrib>Sugita, Shintaro</creatorcontrib><creatorcontrib>Hasegawa, Tadashi</creatorcontrib><creatorcontrib>Takasawa, Akira</creatorcontrib><creatorcontrib>Miyanishi, Koji</creatorcontrib><creatorcontrib>Kobune, Masayoshi</creatorcontrib><creatorcontrib>Kato, Junji</creatorcontrib><collection>Springer Nature OA Free Journals</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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 One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayasaka, Naotaka</au><au>Takada, Kohichi</au><au>Nakamura, Hajime</au><au>Arihara, Yohei</au><au>Kawano, Yutaka</au><au>Osuga, Takahiro</au><au>Murase, Kazuyuki</au><au>Kikuchi, Shohei</au><au>Iyama, Satoshi</au><au>Emori, Makoto</au><au>Sugita, Shintaro</au><au>Hasegawa, Tadashi</au><au>Takasawa, Akira</au><au>Miyanishi, Koji</au><au>Kobune, Masayoshi</au><au>Kato, Junji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-04-08</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>5759</spage><pages>5759-</pages><artnum>5759</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth
in vivo
as well as
in vitro
. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30962488</pmid><doi>10.1038/s41598-019-42300-z</doi><orcidid>https://orcid.org/0000-0003-3828-8444</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/2 13/31 64/60 692/4028/67/1798 692/699/67/1798 82/80 AKT protein Animals Antineoplastic Agents - toxicity Apoptosis Apoptosis - drug effects Breast cancer Caspase Cdc2 protein Cell Cycle Checkpoints Cell Line Cell Line, Tumor Cyclin-dependent kinases Cyclin-Dependent Kinases - genetics Cyclin-Dependent Kinases - metabolism Cyclins Cyclins - genetics Cyclins - metabolism Cytotoxicity Drug Synergism Furans - toxicity Heterocyclic Compounds, 3-Ring - toxicity Humanities and Social Sciences Humans Ketones - toxicity Liposarcoma Metastases Mice Mice, Inbred BALB C multidisciplinary Protein Kinase Inhibitors - toxicity Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Sarcoma Sarcoma - metabolism Science Science (multidisciplinary) Soft Tissue Neoplasms - metabolism Soft tissue sarcoma Tissues Tumors |
| title | Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells |
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