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.
Highlights
Ruthenium-based antineoplastic drugs candidates are coordination complexes of ruthenium that have been reported as alternatives to platinum-based anticancer drugs, due to their reduced side effects, which may be attributed, at least in part, to the ability of this metal to mimic iron in binding to several biological molecules[4,5]
Ru(II)-thymine complex causes DNA damage-mediated apoptotic cell death in HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling
We demonstrated for the first time that the Ru(II)-thymine complex causes DNA damage and apoptotic cell death in HCT116 cells mediated by JNK/p38/ERK1/2 via p53-independent signaling, and inhibits tumor cell growth in xenograft model
Summary
Ruthenium-based antineoplastic drugs candidates are coordination complexes of ruthenium that have been reported as alternatives to platinum-based anticancer drugs, due to their reduced side effects, which may be attributed, at least in part, to the ability of this metal to mimic iron in binding to several biological molecules[4,5]. Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thyminate and bipy = 2,2′-bipyridine) (Fig. 1) was previously described as a potent cytotoxic agent with the ability to bind DNA and human and bovine serum albumins, which induces caspase-mediated apoptosis in leukemia cells[16,17]. In this present study, we investigated the cytotoxic mechanisms underlying cell death of human colon carcinoma HCT116 by the Ru(II)-thymine complex, as well as its effect in xenograft tumor model
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