Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling
Identifieur interne : 000405 ( Pmc/Checkpoint ); précédent : 000404; suivant : 000406Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling
Auteurs : Suellen L. R. Silva ; Ingrid R. S. Baliza ; Rosane B. Dias ; Caroline B. S. Sales ; Clarissa A. Gurgel Rocha ; Milena B. P. Soares ; Rodrigo S. Correa ; Alzir A. Batista ; Daniel P. BezerraSource :
- Scientific Reports [ 2045-2322 ] ; 2019.
Abstract
Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thyminate and bipy = 2,2′-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6–40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.
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DOI: 10.1038/s41598-019-47539-0
PubMed: 31366902
PubMed Central: 6668648
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling</title><author><name sortKey="Silva, Suellen L R" sort="Silva, Suellen L R" uniqKey="Silva S" first="Suellen L. R." last="Silva">Suellen L. R. Silva</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Baliza, Ingrid R S" sort="Baliza, Ingrid R S" uniqKey="Baliza I" first="Ingrid R. S." last="Baliza">Ingrid R. S. 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Correa</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0488 4317</institution-id><institution-id institution-id-type="GRID">grid.411213.4</institution-id><institution>Department of Chemistry,</institution><institution>Federal University of Ouro Preto,</institution></institution-wrap>Ouro Preto, Minas Gerais 35400-000 Brazil</nlm:aff><wicri:noCountry code="subfield">Minas Gerais 35400-000 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Batista, Alzir A" sort="Batista, Alzir A" uniqKey="Batista A" first="Alzir A." last="Batista">Alzir A. 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R." last="Silva">Suellen L. R. Silva</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Baliza, Ingrid R S" sort="Baliza, Ingrid R S" uniqKey="Baliza I" first="Ingrid R. S." last="Baliza">Ingrid R. S. Baliza</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Dias, Rosane B" sort="Dias, Rosane B" uniqKey="Dias R" first="Rosane B." last="Dias">Rosane B. Dias</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Sales, Caroline B S" sort="Sales, Caroline B S" uniqKey="Sales C" first="Caroline B. S." last="Sales">Caroline B. S. Sales</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0372 8259</institution-id><institution-id institution-id-type="GRID">grid.8399.b</institution-id><institution>Department of Biomorphology, Institute of Health Sciences,</institution><institution>Federal University of Bahia,</institution></institution-wrap>Salvador, Bahia 40110-902 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40110-902 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Rocha, Clarissa A Gurgel" sort="Rocha, Clarissa A Gurgel" uniqKey="Rocha C" first="Clarissa A. Gurgel" last="Rocha">Clarissa A. Gurgel Rocha</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Soares, Milena B P" sort="Soares, Milena B P" uniqKey="Soares M" first="Milena B. P." last="Soares">Milena B. P. Soares</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Correa, Rodrigo S" sort="Correa, Rodrigo S" uniqKey="Correa R" first="Rodrigo S." last="Correa">Rodrigo S. Correa</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0488 4317</institution-id><institution-id institution-id-type="GRID">grid.411213.4</institution-id><institution>Department of Chemistry,</institution><institution>Federal University of Ouro Preto,</institution></institution-wrap>Ouro Preto, Minas Gerais 35400-000 Brazil</nlm:aff><wicri:noCountry code="subfield">Minas Gerais 35400-000 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Batista, Alzir A" sort="Batista, Alzir A" uniqKey="Batista A" first="Alzir A." last="Batista">Alzir A. Batista</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2163 588X</institution-id><institution-id institution-id-type="GRID">grid.411247.5</institution-id><institution>Department of Chemistry,</institution><institution>Federal University of São Carlos,</institution></institution-wrap>São Carlos, São Paulo 13561-901 Brazil</nlm:aff><wicri:noCountry code="subfield">São Paulo 13561-901 Brazil</wicri:noCountry></affiliation></author><author><name sortKey="Bezerra, Daniel P" sort="Bezerra, Daniel P" uniqKey="Bezerra D" first="Daniel P." last="Bezerra">Daniel P. Bezerra</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</nlm:aff><wicri:noCountry code="subfield">Bahia 40296-710 Brazil</wicri:noCountry></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Ru(II)-thymine complex [Ru(PPh<sub>3</sub>)<sub>2</sub>(Thy)(bipy)]PF<sub>6</sub> (where PPh<sub>3</sub> = triphenylphosphine, Thy = thyminate and bipy = 2,2′-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6–40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ciombor, Kk" uniqKey="Ciombor K">KK Ciombor</name></author><author><name sortKey="Wu, C" uniqKey="Wu C">C Wu</name></author><author><name sortKey="Goldberg, Rm" uniqKey="Goldberg R">RM Goldberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Iveson, Tj" uniqKey="Iveson T">TJ Iveson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sava, G" uniqKey="Sava G">G Sava</name></author><author><name sortKey="Bergamo, A" uniqKey="Bergamo A">A Bergamo</name></author><author><name sortKey="Dyson, Pj" uniqKey="Dyson P">PJ Dyson</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31366902</article-id><article-id pub-id-type="pmc">6668648</article-id><article-id pub-id-type="publisher-id">47539</article-id><article-id pub-id-type="doi">10.1038/s41598-019-47539-0</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Silva</surname><given-names>Suellen L. R.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Baliza</surname><given-names>Ingrid R. S.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dias</surname><given-names>Rosane B.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sales</surname><given-names>Caroline B. S.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rocha</surname><given-names>Clarissa A. Gurgel</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Soares</surname><given-names>Milena B. P.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Correa</surname><given-names>Rodrigo S.</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Batista</surname><given-names>Alzir A.</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-6774-2063</contrib-id><name><surname>Bezerra</surname><given-names>Daniel P.</given-names></name><address><email>danielpbezerra@gmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0723 0931</institution-id><institution-id institution-id-type="GRID">grid.418068.3</institution-id><institution>Gonçalo Moniz Institute,</institution><institution>Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA),</institution></institution-wrap>Salvador, Bahia 40296-710 Brazil</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0372 8259</institution-id><institution-id institution-id-type="GRID">grid.8399.b</institution-id><institution>Department of Biomorphology, Institute of Health Sciences,</institution><institution>Federal University of Bahia,</institution></institution-wrap>Salvador, Bahia 40110-902 Brazil</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0488 4317</institution-id><institution-id institution-id-type="GRID">grid.411213.4</institution-id><institution>Department of Chemistry,</institution><institution>Federal University of Ouro Preto,</institution></institution-wrap>Ouro Preto, Minas Gerais 35400-000 Brazil</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2163 588X</institution-id><institution-id institution-id-type="GRID">grid.411247.5</institution-id><institution>Department of Chemistry,</institution><institution>Federal University of São Carlos,</institution></institution-wrap>São Carlos, São Paulo 13561-901 Brazil</aff></contrib-group><pub-date pub-type="epub"><day>31</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>31</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>9</volume><elocation-id>11094</elocation-id><history><date date-type="received"><day>7</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Ru(II)-thymine complex [Ru(PPh<sub>3</sub>)<sub>2</sub>(Thy)(bipy)]PF<sub>6</sub> (where PPh<sub>3</sub> = triphenylphosphine, Thy = thyminate and bipy = 2,2′-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6–40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Pharmacology</kwd><kwd>Drug development</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001807</institution-id><institution>Fundação de Amparo à Pesquisa do Estado de São Paulo (São Paulo Research Foundation)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100003593</institution-id><institution>Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100002322</institution-id><institution>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education)</institution></institution-wrap></funding-source></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100006181</institution-id><institution>Fundação de Amparo à Pesquisa do Estado da Bahia (Foundation for Research Support of the State of Bahia)</institution></institution-wrap></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Baliza, Ingrid R S" sort="Baliza, Ingrid R S" uniqKey="Baliza I" first="Ingrid R. S." last="Baliza">Ingrid R. S. Baliza</name><name sortKey="Batista, Alzir A" sort="Batista, Alzir A" uniqKey="Batista A" first="Alzir A." last="Batista">Alzir A. Batista</name><name sortKey="Bezerra, Daniel P" sort="Bezerra, Daniel P" uniqKey="Bezerra D" first="Daniel P." last="Bezerra">Daniel P. Bezerra</name><name sortKey="Correa, Rodrigo S" sort="Correa, Rodrigo S" uniqKey="Correa R" first="Rodrigo S." last="Correa">Rodrigo S. Correa</name><name sortKey="Dias, Rosane B" sort="Dias, Rosane B" uniqKey="Dias R" first="Rosane B." last="Dias">Rosane B. Dias</name><name sortKey="Rocha, Clarissa A Gurgel" sort="Rocha, Clarissa A Gurgel" uniqKey="Rocha C" first="Clarissa A. Gurgel" last="Rocha">Clarissa A. Gurgel Rocha</name><name sortKey="Sales, Caroline B S" sort="Sales, Caroline B S" uniqKey="Sales C" first="Caroline B. S." last="Sales">Caroline B. S. Sales</name><name sortKey="Silva, Suellen L R" sort="Silva, Suellen L R" uniqKey="Silva S" first="Suellen L. R." last="Silva">Suellen L. R. Silva</name><name sortKey="Soares, Milena B P" sort="Soares, Milena B P" uniqKey="Soares M" first="Milena B. P." last="Soares">Milena B. P. Soares</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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