Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation
The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cel...
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| Veröffentlicht in: | Scientific reports 2018-03, Vol.8 (1), p.4370-18, Article 4370 |
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| creator | Bort, Alicia Quesada, Sergio Ramos-Torres, Ágata Gargantilla, Marta Priego, Eva María Raynal, Sophie Lepifre, Franck Gasalla, Jose M. Rodriguez-Henche, Nieves Castro, Ana Díaz-Laviada, Inés |
| description | The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound
8c
, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound
8c
caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as
in vitro
assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound
8c
exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound
8c
was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent
in vivo
antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer. |
| doi_str_mv | 10.1038/s41598-018-22690-2 |
| format | Article |
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8c
, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound
8c
caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as
in vitro
assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound
8c
exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound
8c
was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent
in vivo
antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-22690-2</identifier><identifier>PMID: 29531259</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059 ; 692/308/153 ; 692/4017 ; 82 ; 82/80 ; 96/1 ; 96/109 ; 96/95 ; Adenosine kinase ; AMP ; AMP-Activated Protein Kinases - metabolism ; Androgens ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Autophagy ; Cell cycle ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Energy balance ; Halogenation ; Homeostasis ; Humanities and Social Sciences ; Humans ; Isoforms ; Male ; Metabolic rate ; multidisciplinary ; Oxindoles - chemical synthesis ; Oxindoles - chemistry ; Oxindoles - pharmacology ; Phagocytosis ; Phosphorylation ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Protein Isoforms ; Science ; Science (multidisciplinary) ; Therapeutic applications ; Tumors ; Xenografts</subject><ispartof>Scientific reports, 2018-03, Vol.8 (1), p.4370-18, Article 4370</ispartof><rights>The Author(s) 2018</rights><rights>2018. 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-c474t-563d367e824d74b738eac781bb4032607b523faaa82cb3a5e1054dada1a662e13</citedby><cites>FETCH-LOGICAL-c474t-563d367e824d74b738eac781bb4032607b523faaa82cb3a5e1054dada1a662e13</cites><orcidid>0000-0001-9704-4373 ; 0000-0001-9470-4508</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/PMC5847527/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847527/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29531259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bort, Alicia</creatorcontrib><creatorcontrib>Quesada, Sergio</creatorcontrib><creatorcontrib>Ramos-Torres, Ágata</creatorcontrib><creatorcontrib>Gargantilla, Marta</creatorcontrib><creatorcontrib>Priego, Eva María</creatorcontrib><creatorcontrib>Raynal, Sophie</creatorcontrib><creatorcontrib>Lepifre, Franck</creatorcontrib><creatorcontrib>Gasalla, Jose M.</creatorcontrib><creatorcontrib>Rodriguez-Henche, Nieves</creatorcontrib><creatorcontrib>Castro, Ana</creatorcontrib><creatorcontrib>Díaz-Laviada, Inés</creatorcontrib><title>Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound
8c
, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound
8c
caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as
in vitro
assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound
8c
exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound
8c
was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent
in vivo
antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.</description><subject>631/67/1059</subject><subject>692/308/153</subject><subject>692/4017</subject><subject>82</subject><subject>82/80</subject><subject>96/1</subject><subject>96/109</subject><subject>96/95</subject><subject>Adenosine kinase</subject><subject>AMP</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Androgens</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Autophagy</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Energy balance</subject><subject>Halogenation</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Isoforms</subject><subject>Male</subject><subject>Metabolic rate</subject><subject>multidisciplinary</subject><subject>Oxindoles - chemical synthesis</subject><subject>Oxindoles - chemistry</subject><subject>Oxindoles - pharmacology</subject><subject>Phagocytosis</subject><subject>Phosphorylation</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Protein Isoforms</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Therapeutic applications</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kUFvFSEQx4nR2Kb2C3gwJF68rMIAy-7FpGmqNtboQc9kFtgnzT54wu5GP4DfW_perdWDXBgyv_nPDH9CnnL2kjPRvSqSq75rGO8agLZnDTwgx8CkakAAPLwXH5HTUq5ZPQp6yfvH5Ah6JTio_pj8vHQ-zmEMFueQIk0jRRrT6icKTfoeokuTp-O0pBwizt5R53NYK7x6ioWGSNewJopVZF62KVPcVEE61miXU5lrDbUYra8ZO4e4qTzSsw-f3u_f677tE_JoxKn409v7hHx5c_H5_F1z9fHt5fnZVWOllnOjWuFEq30H0mk5aNF5tLrjwyCZgJbpQYEYEbEDOwhUnjMlHTrk2LbguTghrw-6u2XYemfrpBkns8thi_mHSRjM35kYvppNWo3qpFagq8CLW4Gcvi2-zGYbivXThNGnpRhgXCiuVHuDPv8HvU5LjnW9PcUlMM0qBQfK1s8q2Y93w3Bmbow2B6NNNdrsjTZQi57dX-Ou5LetFRAHoNRU3Pj8p_d_ZH8BrM61qg</recordid><startdate>20180312</startdate><enddate>20180312</enddate><creator>Bort, Alicia</creator><creator>Quesada, Sergio</creator><creator>Ramos-Torres, Ágata</creator><creator>Gargantilla, Marta</creator><creator>Priego, Eva María</creator><creator>Raynal, Sophie</creator><creator>Lepifre, Franck</creator><creator>Gasalla, Jose M.</creator><creator>Rodriguez-Henche, Nieves</creator><creator>Castro, Ana</creator><creator>Díaz-Laviada, Inés</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9704-4373</orcidid><orcidid>https://orcid.org/0000-0001-9470-4508</orcidid></search><sort><creationdate>20180312</creationdate><title>Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation</title><author>Bort, Alicia ; Quesada, Sergio ; Ramos-Torres, Ágata ; Gargantilla, Marta ; Priego, Eva María ; Raynal, Sophie ; Lepifre, Franck ; Gasalla, Jose M. ; Rodriguez-Henche, Nieves ; Castro, Ana ; Díaz-Laviada, Inés</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-563d367e824d74b738eac781bb4032607b523faaa82cb3a5e1054dada1a662e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>631/67/1059</topic><topic>692/308/153</topic><topic>692/4017</topic><topic>82</topic><topic>82/80</topic><topic>96/1</topic><topic>96/109</topic><topic>96/95</topic><topic>Adenosine kinase</topic><topic>AMP</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Androgens</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Autophagy</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Energy balance</topic><topic>Halogenation</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Isoforms</topic><topic>Male</topic><topic>Metabolic rate</topic><topic>multidisciplinary</topic><topic>Oxindoles - chemical synthesis</topic><topic>Oxindoles - chemistry</topic><topic>Oxindoles - pharmacology</topic><topic>Phagocytosis</topic><topic>Phosphorylation</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Protein Isoforms</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Therapeutic applications</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bort, Alicia</creatorcontrib><creatorcontrib>Quesada, Sergio</creatorcontrib><creatorcontrib>Ramos-Torres, Ágata</creatorcontrib><creatorcontrib>Gargantilla, Marta</creatorcontrib><creatorcontrib>Priego, Eva María</creatorcontrib><creatorcontrib>Raynal, Sophie</creatorcontrib><creatorcontrib>Lepifre, Franck</creatorcontrib><creatorcontrib>Gasalla, Jose M.</creatorcontrib><creatorcontrib>Rodriguez-Henche, Nieves</creatorcontrib><creatorcontrib>Castro, Ana</creatorcontrib><creatorcontrib>Díaz-Laviada, Inés</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</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>MEDLINE - Academic</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>Bort, Alicia</au><au>Quesada, Sergio</au><au>Ramos-Torres, Ágata</au><au>Gargantilla, Marta</au><au>Priego, Eva María</au><au>Raynal, Sophie</au><au>Lepifre, Franck</au><au>Gasalla, Jose M.</au><au>Rodriguez-Henche, Nieves</au><au>Castro, Ana</au><au>Díaz-Laviada, Inés</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-03-12</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>4370</spage><epage>18</epage><pages>4370-18</pages><artnum>4370</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound
8c
, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound
8c
caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as
in vitro
assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound
8c
exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound
8c
was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent
in vivo
antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29531259</pmid><doi>10.1038/s41598-018-22690-2</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-9704-4373</orcidid><orcidid>https://orcid.org/0000-0001-9470-4508</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1059 692/308/153 692/4017 82 82/80 96/1 96/109 96/95 Adenosine kinase AMP AMP-Activated Protein Kinases - metabolism Androgens Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Autophagy Cell cycle Cell Line, Tumor Cell Proliferation - drug effects Energy balance Halogenation Homeostasis Humanities and Social Sciences Humans Isoforms Male Metabolic rate multidisciplinary Oxindoles - chemical synthesis Oxindoles - chemistry Oxindoles - pharmacology Phagocytosis Phosphorylation Prostate cancer Prostatic Neoplasms - drug therapy Protein Isoforms Science Science (multidisciplinary) Therapeutic applications Tumors Xenografts |
| title | Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation |
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