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 : 000866 ( Ncbi/Checkpoint ); précédent : 000865; suivant : 000867Ru(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.
Url:
DOI: 10.1038/s41598-019-47539-0
PubMed: 31366902
PubMed Central: 6668648
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">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>
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<series><title level="j">Scientific Reports</title>
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<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>
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<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>
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