Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells
Ruthenium(II) complexes with 6-methyl-2-thiouracil cis -[Ru(6m2tu) 2 (PPh 3 ) 2 ] ( 1 ) and [Ru(6m2tu) 2 (dppb)] ( 2 ) (where PPh 3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this stu...
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| creator | Bomfim, Larissa M. de Araujo, Fênix A. Dias, Rosane B. Sales, Caroline B. S. Rocha, Clarissa A. Gurgel Correa, Rodrigo S. Soares, Milena B. P. Batista, Alzir A. Bezerra, Daniel P. |
| description | Ruthenium(II) complexes with 6-methyl-2-thiouracil
cis
-[Ru(6m2tu)
2
(PPh
3
)
2
] (
1
) and [Ru(6m2tu)
2
(dppb)] (
2
) (where PPh
3 =
triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate
in vitro
cellular underlying mechanism and
in vivo
effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex
1
also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates. |
| doi_str_mv | 10.1038/s41598-019-47914-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6686011</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2269410501</sourcerecordid><originalsourceid>FETCH-LOGICAL-c513t-1e45265e4c54c89e09b8ed964b28cb16629e0573660e235193a150d3b364bc253</originalsourceid><addsrcrecordid>eNp9Ustu1DAUjRCIVqU_wAJZYgMSpn7EbrJBqsproCoSgrXlOHcmbp049aOd-V5-BE-nlLLBG1u-555zH6eqnlPylhLeHMWairbBhLa4Pm5pjdePqn1GaoEZZ-zxg_dedRjjBSlHsLam7dNqj1PeUkHIfvXre04DTDaPrxaL18j4cXawhohubBqQxCOkYeMww2mwPgdtrEMRHJhkr8FtUIA-G0AGnENz8M4uIehk_fQGGZ0joPfnJ6j3uXOAYwp66lEXQF-i7SsFu1pBKMg46whFrLc6QY_07Ofko40oDcHn1YC-nH89mnmDZp2GG72JyE5oyKOekDY5wVZ73IDzZpOsQQ7yJYxW39YVn1VPltpFOLy7D6qfHz_8OP2Mz759WpyenGEjKE-YQi2YFFAbUZumBdJ2DfStrDvWmI5KycqfOOZSEmBc0JbrMsOed7xADBP8oHq3451zV1oxMJWGnZqDHXXYKK-t-jcy2UGt_LWSspGE0kLw8o4g-KsMMamLMvOp1KwYk2V3RJAtiu1QJvgYAyzvFShRW2-onTdU8Ya69YZal6QXD2u7T_njhALgO0Asoals5a_2f2h_A8JTysE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2269410501</pqid></control><display><type>article</type><title>Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Bomfim, Larissa M. ; de Araujo, Fênix A. ; Dias, Rosane B. ; Sales, Caroline B. S. ; Rocha, Clarissa A. Gurgel ; Correa, Rodrigo S. ; Soares, Milena B. P. ; Batista, Alzir A. ; Bezerra, Daniel P.</creator><creatorcontrib>Bomfim, Larissa M. ; de Araujo, Fênix A. ; Dias, Rosane B. ; Sales, Caroline B. S. ; Rocha, Clarissa A. Gurgel ; Correa, Rodrigo S. ; Soares, Milena B. P. ; Batista, Alzir A. ; Bezerra, Daniel P.</creatorcontrib><description>Ruthenium(II) complexes with 6-methyl-2-thiouracil
cis
-[Ru(6m2tu)
2
(PPh
3
)
2
] (
1
) and [Ru(6m2tu)
2
(dppb)] (
2
) (where PPh
3 =
triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate
in vitro
cellular underlying mechanism and
in vivo
effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex
1
also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-47914-x</identifier><identifier>PMID: 31391500</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/2 ; 13/31 ; 14/28 ; 631/154/436 ; 64/110 ; 692/4028/67/1990 ; Acute promyeloid leukemia ; Animals ; Apoptosis ; Apoptosis - drug effects ; Butane ; Caspase inhibitors ; Caspase-3 ; Caspases - metabolism ; Cell growth ; Cell proliferation ; Cell Proliferation - drug effects ; Coordination Complexes - pharmacology ; Coordination Complexes - therapeutic use ; Cytotoxic agents ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded - drug effects ; DNA damage ; Drug development ; Female ; Histone H2A ; HL-60 Cells ; Humanities and Social Sciences ; Humans ; Leukemia ; Leukemia, Promyelocytic, Acute ; MAP kinase ; MAP Kinase Signaling System - drug effects ; Membrane potential ; Metal complexes ; Mice ; Mitochondria ; multidisciplinary ; Myeloid leukemia ; Phosphatidylserine ; Phosphorylation ; Phosphorylation - drug effects ; Promyeloid leukemia ; Ruthenium ; Ruthenium - pharmacology ; Ruthenium - therapeutic use ; Science ; Science (multidisciplinary) ; Thiouracil - analogs & derivatives ; Thiouracil - pharmacology ; Thiouracil - therapeutic use ; Tumor cell lines ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Scientific reports, 2019-08, Vol.9 (1), p.11483-17, Article 11483</ispartof><rights>The Author(s) 2019</rights><rights>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-c513t-1e45265e4c54c89e09b8ed964b28cb16629e0573660e235193a150d3b364bc253</citedby><cites>FETCH-LOGICAL-c513t-1e45265e4c54c89e09b8ed964b28cb16629e0573660e235193a150d3b364bc253</cites><orcidid>0000-0002-6774-2063</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/PMC6686011/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686011/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51555,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31391500$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bomfim, Larissa M.</creatorcontrib><creatorcontrib>de Araujo, Fênix A.</creatorcontrib><creatorcontrib>Dias, Rosane B.</creatorcontrib><creatorcontrib>Sales, Caroline B. S.</creatorcontrib><creatorcontrib>Rocha, Clarissa A. Gurgel</creatorcontrib><creatorcontrib>Correa, Rodrigo S.</creatorcontrib><creatorcontrib>Soares, Milena B. P.</creatorcontrib><creatorcontrib>Batista, Alzir A.</creatorcontrib><creatorcontrib>Bezerra, Daniel P.</creatorcontrib><title>Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Ruthenium(II) complexes with 6-methyl-2-thiouracil
cis
-[Ru(6m2tu)
2
(PPh
3
)
2
] (
1
) and [Ru(6m2tu)
2
(dppb)] (
2
) (where PPh
3 =
triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate
in vitro
cellular underlying mechanism and
in vivo
effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex
1
also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.</description><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/31</subject><subject>14/28</subject><subject>631/154/436</subject><subject>64/110</subject><subject>692/4028/67/1990</subject><subject>Acute promyeloid leukemia</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Butane</subject><subject>Caspase inhibitors</subject><subject>Caspase-3</subject><subject>Caspases - metabolism</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Coordination Complexes - pharmacology</subject><subject>Coordination Complexes - therapeutic use</subject><subject>Cytotoxic agents</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded - drug effects</subject><subject>DNA damage</subject><subject>Drug development</subject><subject>Female</subject><subject>Histone H2A</subject><subject>HL-60 Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemia, Promyelocytic, Acute</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Membrane potential</subject><subject>Metal complexes</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>multidisciplinary</subject><subject>Myeloid leukemia</subject><subject>Phosphatidylserine</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Promyeloid leukemia</subject><subject>Ruthenium</subject><subject>Ruthenium - pharmacology</subject><subject>Ruthenium - therapeutic use</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Thiouracil - analogs & derivatives</subject><subject>Thiouracil - pharmacology</subject><subject>Thiouracil - therapeutic use</subject><subject>Tumor cell lines</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</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>eNp9Ustu1DAUjRCIVqU_wAJZYgMSpn7EbrJBqsproCoSgrXlOHcmbp049aOd-V5-BE-nlLLBG1u-555zH6eqnlPylhLeHMWairbBhLa4Pm5pjdePqn1GaoEZZ-zxg_dedRjjBSlHsLam7dNqj1PeUkHIfvXre04DTDaPrxaL18j4cXawhohubBqQxCOkYeMww2mwPgdtrEMRHJhkr8FtUIA-G0AGnENz8M4uIehk_fQGGZ0joPfnJ6j3uXOAYwp66lEXQF-i7SsFu1pBKMg46whFrLc6QY_07Ofko40oDcHn1YC-nH89mnmDZp2GG72JyE5oyKOekDY5wVZ73IDzZpOsQQ7yJYxW39YVn1VPltpFOLy7D6qfHz_8OP2Mz759WpyenGEjKE-YQi2YFFAbUZumBdJ2DfStrDvWmI5KycqfOOZSEmBc0JbrMsOed7xADBP8oHq3451zV1oxMJWGnZqDHXXYKK-t-jcy2UGt_LWSspGE0kLw8o4g-KsMMamLMvOp1KwYk2V3RJAtiu1QJvgYAyzvFShRW2-onTdU8Ya69YZal6QXD2u7T_njhALgO0Asoals5a_2f2h_A8JTysE</recordid><startdate>20190807</startdate><enddate>20190807</enddate><creator>Bomfim, Larissa M.</creator><creator>de Araujo, Fênix A.</creator><creator>Dias, Rosane B.</creator><creator>Sales, Caroline B. S.</creator><creator>Rocha, Clarissa A. Gurgel</creator><creator>Correa, Rodrigo S.</creator><creator>Soares, Milena B. P.</creator><creator>Batista, Alzir A.</creator><creator>Bezerra, Daniel P.</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/0000-0002-6774-2063</orcidid></search><sort><creationdate>20190807</creationdate><title>Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells</title><author>Bomfim, Larissa M. ; de Araujo, Fênix A. ; Dias, Rosane B. ; Sales, Caroline B. S. ; Rocha, Clarissa A. Gurgel ; Correa, Rodrigo S. ; Soares, Milena B. P. ; Batista, Alzir A. ; Bezerra, Daniel P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-1e45265e4c54c89e09b8ed964b28cb16629e0573660e235193a150d3b364bc253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/2</topic><topic>13/31</topic><topic>14/28</topic><topic>631/154/436</topic><topic>64/110</topic><topic>692/4028/67/1990</topic><topic>Acute promyeloid leukemia</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Butane</topic><topic>Caspase inhibitors</topic><topic>Caspase-3</topic><topic>Caspases - metabolism</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Coordination Complexes - pharmacology</topic><topic>Coordination Complexes - therapeutic use</topic><topic>Cytotoxic agents</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded - drug effects</topic><topic>DNA damage</topic><topic>Drug development</topic><topic>Female</topic><topic>Histone H2A</topic><topic>HL-60 Cells</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Leukemia, Promyelocytic, Acute</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Membrane potential</topic><topic>Metal complexes</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>multidisciplinary</topic><topic>Myeloid leukemia</topic><topic>Phosphatidylserine</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Promyeloid leukemia</topic><topic>Ruthenium</topic><topic>Ruthenium - pharmacology</topic><topic>Ruthenium - therapeutic use</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Thiouracil - analogs & derivatives</topic><topic>Thiouracil - pharmacology</topic><topic>Thiouracil - therapeutic use</topic><topic>Tumor cell lines</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bomfim, Larissa M.</creatorcontrib><creatorcontrib>de Araujo, Fênix A.</creatorcontrib><creatorcontrib>Dias, Rosane B.</creatorcontrib><creatorcontrib>Sales, Caroline B. S.</creatorcontrib><creatorcontrib>Rocha, Clarissa A. Gurgel</creatorcontrib><creatorcontrib>Correa, Rodrigo S.</creatorcontrib><creatorcontrib>Soares, Milena B. P.</creatorcontrib><creatorcontrib>Batista, Alzir A.</creatorcontrib><creatorcontrib>Bezerra, Daniel P.</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>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bomfim, Larissa M.</au><au>de Araujo, Fênix A.</au><au>Dias, Rosane B.</au><au>Sales, Caroline B. S.</au><au>Rocha, Clarissa A. Gurgel</au><au>Correa, Rodrigo S.</au><au>Soares, Milena B. P.</au><au>Batista, Alzir A.</au><au>Bezerra, Daniel P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-08-07</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>11483</spage><epage>17</epage><pages>11483-17</pages><artnum>11483</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Ruthenium(II) complexes with 6-methyl-2-thiouracil
cis
-[Ru(6m2tu)
2
(PPh
3
)
2
] (
1
) and [Ru(6m2tu)
2
(dppb)] (
2
) (where PPh
3 =
triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate
in vitro
cellular underlying mechanism and
in vivo
effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex
1
also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31391500</pmid><doi>10.1038/s41598-019-47914-x</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-6774-2063</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Scientific reports, 2019-08, Vol.9 (1), p.11483-17, Article 11483 |
| issn | 2045-2322 2045-2322 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6686011 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | 13/1 13/106 13/2 13/31 14/28 631/154/436 64/110 692/4028/67/1990 Acute promyeloid leukemia Animals Apoptosis Apoptosis - drug effects Butane Caspase inhibitors Caspase-3 Caspases - metabolism Cell growth Cell proliferation Cell Proliferation - drug effects Coordination Complexes - pharmacology Coordination Complexes - therapeutic use Cytotoxic agents Cytotoxicity Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded - drug effects DNA damage Drug development Female Histone H2A HL-60 Cells Humanities and Social Sciences Humans Leukemia Leukemia, Promyelocytic, Acute MAP kinase MAP Kinase Signaling System - drug effects Membrane potential Metal complexes Mice Mitochondria multidisciplinary Myeloid leukemia Phosphatidylserine Phosphorylation Phosphorylation - drug effects Promyeloid leukemia Ruthenium Ruthenium - pharmacology Ruthenium - therapeutic use Science Science (multidisciplinary) Thiouracil - analogs & derivatives Thiouracil - pharmacology Thiouracil - therapeutic use Tumor cell lines Xenograft Model Antitumor Assays Xenografts |
| title | Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T14%3A21%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ruthenium(II)%20complexes%20with%206-methyl-2-thiouracil%20selectively%20reduce%20cell%20proliferation,%20cause%20DNA%20double-strand%20break%20and%20trigger%20caspase-mediated%20apoptosis%20through%20JNK/p38%20pathways%20in%20human%20acute%20promyelocytic%20leukemia%20cells&rft.jtitle=Scientific%20reports&rft.au=Bomfim,%20Larissa%20M.&rft.date=2019-08-07&rft.volume=9&rft.issue=1&rft.spage=11483&rft.epage=17&rft.pages=11483-17&rft.artnum=11483&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-019-47914-x&rft_dat=%3Cproquest_pubme%3E2269410501%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2269410501&rft_id=info:pmid/31391500&rfr_iscdi=true |