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 : 000449 ( Main/Exploration ); précédent : 000448; suivant : 000450Ru(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
Affiliations:
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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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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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Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Purushothaman, B" uniqKey="Purushothaman B">B Purushothaman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><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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