Abstract
In this study, we compared the effect of tricarbonyldichlororuthenium (II) dimer (CORM-2) and its CO-depleted molecule (iCORM-2) on human peripheral blood mononuclear cells (PBMCs) and human promyelocytic leukemia HL-60 cells. We determined cell viability, DNA damage and DNA repair kinetics. We also studied the effect of both compounds on DNA oxidative damage, free radical level and HO-1 gene expression. We showed that at low concentrations both CORM-2 and iCORM-2 stimulate PBMCs viability. After 24-h incubation, CORM-2 and iCORM-2, at the concentration of 100 µM, reduce the viability of both PBMCs and HL-60 cells. We also demonstrated that CORM-2 and iCORM-2, in the 0.01–100 µM concentration range, cause DNA damage such as strand breaks and alkaline labile sites. DNA damage was repaired efficiently only in HL-60 cells. CORM-2 significantly reduces oxidative stress induced by 1 mM H2O2 in normal and cancer cells. On the contrary, iCORM-2 in HL-60 cells increases the level of free radicals in the presence of 1 and 5 mM H2O2. We also revealed that both CORM-2 and iCORM-2 induce HO-1 gene expression. However, CORM-2 induces this gene to a greater extent than iCORM-2, especially in HL-60 cells at 100 µM. Finally, we showed that CORM-2 and iCORM-2 reduce H2O2-induced DNA oxidative damage. Furthermore, CORM-2 proved to be a compound with stronger antioxidant properties than iCORM-2. Our results suggest that both active CORM-2 and inactive iCORM-2 exert biological effects such as cyto- and genotoxicity, antioxidant properties and the ability to induce the HO-1 gene. The released CO as well as iCORM-2 can be responsible for these effects.
Highlights
In this study, we compared the effect of tricarbonyldichlororuthenium (II) dimer (CORM-2) and its Carbon monoxide (CO)-depleted molecule on human peripheral blood mononuclear cells (PBMCs) and human promyelocytic leukemia HL-60 cells
Our results indicate that CO released from Carbon Monoxide-Releasing Molecules (CORMs)-2 at a low concentration can increase cell viability
We observed a significant increase in the level of DNA damage in PBMCs incubated with CORM-2 and inactivated CORMs (iCORMs)-2 compared to dimethyl sulfoxide (DMSO) (Fig. 3A)
Summary
We compared the effect of tricarbonyldichlororuthenium (II) dimer (CORM-2) and its CO-depleted molecule (iCORM-2) on human peripheral blood mononuclear cells (PBMCs) and human promyelocytic leukemia HL-60 cells. After 24-h incubation, CORM-2 and iCORM-2, at the concentration of 100 μM, reduce the viability of both PBMCs and HL-60 cells. CORM-2 significantly reduces oxidative stress induced by 1 mM H2O2 in normal and cancer cells. We showed that CORM-2 and iCORM-2 reduce H2O2-induced DNA oxidative damage. Our results suggest that both active CORM-2 and inactive iCORM-2 exert biological effects such as cyto- and genotoxicity, antioxidant properties and the ability to induce the HO-1 gene. Trans-[RuCl2(CO)2(DMSO)2] [2] isomer slowly converts to the more stable all cis isomer 3,4 These final decomposition products are commonly called inactivated CORMs (iCORMs), but may have own biological activity. It was shown that CO released by CORM-2 inhibited proliferation and invasion, as well as induced apoptosis in human prostate cancer cell lines − LNCaP and PC-319. A recent study indicates that among the commercially available CORMs (CORM-1, CORM-2 and CORM-A1) CORM-2 has the largest anti-angiogenic potential for triple-negative breast cancer (TNBC)[14]
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