Oxidative stress in tumor-bearing animals and self-dependent antitumor effect of metal nanoparticles.
Authors: Kachesova Polina S. , Goroshinskaya Irina A. , Shalashnaya Elena V. , Zhukova Galina V. , Nemashkalova Ludmila A. , Andreyko Elena A. , Ausheva Tatiana V. , Kechedzhieva Emma E. , Borodulin Vladimir B. , Malinin Sergey A. , Kaminskiy Gennadiy V. , Chalkhakhyan Lusegen Kh. , Ardzha Anna Yu , Kit Oleg I. 
Published: June 2022

e15055

Background: Enhanced generation of reactive oxygen species (ROS) is an important factor in cell damage when exposed to metal nanoparticles (NPs), which can be used to develop antitumor strategies based on ROS level modulation. However, an increase in ROS can cause oxidative stress in the body. The aim of this study was to evaluate the parameters of the redox-regulating system in the blood erythrocytes of tumor-bearing rats at different efficiencies of exposure to copper NPs (CuNPs) and iron NPs (FeNPs). Methods: Outbred male rats with transplantable fusiform cell fibrosarcoma (S45) were treated with copper (group S45+CuNPs, n = 37) or iron NPs (group S45+FeNPs, n = 33). During 15 days, 35 rats received 8 intratumoral injections and 35 rats received 8 intraperitoneal injections of NPs in total doses of 10 mg/kg bw, the control S45 rats (n = 20) received saline i.p. Levels of malondialdehyde (MDA) and glutathione (GSH), the activities of catalase (CA), superoxide dismutase (SOD), and glutathione peroxidase (GPO) in the red blood cells were determined one week after the end of the treatment. Results: Complete or near complete tumor regression was recorded in 13 (35 %) rats with CuNPs treatment and 6 (27%) rats with FeNPs treatment. Decrease in tumor size by 30 to 80% in 14 (38%) rats in CuNPs group and in 14 (43%) rats in FeNPs group was observed. In other cases, tumor growth in rats with S45 treated with metal nanoparticles was similar to animals in the control group. The values of the studied parameters in rats with complete tumor regression after exposure to CuNPs did not differ from those in the group of healthy rats. Unidirectional changes in the studied parameters were observed in rats with partial S45 regression or with no effect. GPO activity increased by 43-57% (p = 0.02-0.002) and GSH level by 20-27% (p = 0.034-0.005), but MDA level was 62-65% (p = 0.027-0.007) higher than normal values. Animals with complete tumor regression after the administration of FeNPs showed changes in the activity of peroxide-inactivating enzymes: an increase in GPO by 84% (p = 0.009) and a decrease in catalase by 31% (p = 0.016) relative to normal values. In animals with partial response or without response, GPO activity increased by 75% and 57%, respectively (p = 0.031-0.042), while CA activity decreased by an average of 37% (p = 0.002-0.0002). No increase in MDA was observed in the S45+FeNPs group. The levels of MDA in rats of the control group were increased by 46% (p = 0.0032), which was combined with an increase in GSH by 19%, a decrease in catalase activity by 16%, and an increase in GPO activity by 41% (p˂0.05 in all cases), compared to the values in intact animals. Conclusions: Regardless of the route of administration, copper and iron NPs did not cause an increase in oxidative stress in rats with fibrosarcoma. The maximum antitumor effect of metal NPs was accompanied by normalization or positive reorganization of the redox-regulating system of erythrocytes.