Abstract
Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh3)2(Thy)(bipy)]PF6 complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh3)2(Thy)(bipy)]PF6 complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells.
Highlights
Cancer is a great public health problem in both developed and developing countries
Ruthenium-based compounds form a class of potential antineoplastic drugs
In studies of the underlying cytotoxic mechanism, we observed the morphology associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability changes, a loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation in complex-treated HL-60 cells
Summary
Cancer is a great public health problem in both developed and developing countries. In 2012, the estimate was approximately 14.1 million new cancer cases and 8.2 million deaths worldwide; among cancer, leukemia has one of the highest incidences worldwide, with approximately 352,000 new cases being diagnosed and approximately 265,500 deaths [1]. The [Ru(PPh3)2(Thy)(bipy)]PF6 Complex Triggers Caspase-Mediated Apoptosis in HL-60 Cells. Inhibitor, Z-VAD(OMe)-FMK, partially prevented the complex-induced increase in apoptotic cells (Figure 7), indicating the induction of caspase-mediated apoptosis in HL-60 cells by the [Ru(PPh3)2(Thy)(bipy)]PF6 complex. Paigpelar[t8i]n.e-Pcoipnltaaritniinneg-crounthtaeinniiunmg ruthenium complexes induce caspase-dependent and intrinsic mitochondrial apoptosis in HCT116 cells through a ROS-mediated pathway [5]. The ruthenium-based 5-fluorouracil complex induces caspase-mediated apoptosis in HCT116 cells [10]. The [Ru(PPh3)2(Thy)(bipy)]PF6 complex did not induce a significant increase in ROS levels after 1 or 3 h of incubation at the tested concentrations (data not shown). In studies of the underlying cytotoxic mechanism, we observed the morphology associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability changes, a loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation in complex-treated HL-60 cells. The pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, which is a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through caspase-mediated pathways
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