A pronounced cytotoxic action of the newly synthesized thiazole derivative N-(5-Benzyl-1,3- thiazole-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide (compound 1) on the tumour cells has been found in vitro earlier, but cytotoxicity of this substance has not been detected in relation to non-cancerous cells. In addition, it has been determined that the scavengers of active forms of oxygen significantly reduce the cytotoxic effect of the compound 1. In this study the influence of compound 1 on the activity of superoxide dismutase and catalase in the mouse Nemeth-Kellner lymphoma (NK/Ly) cells and hepatocytes has been studied in order to evaluate the possible role of the antioxidant activity during the action of a substance. The experiments have been performed using two groups of nonlinear male rats weighing 20-30 g. Rats from the first group have had grafted lymphoma and rats from the second group have been healthy. The ascites form of lymphoma has been caused by the intraperitoneal inoculation of 10-15 million cancer cells in the rats. Thiazole derivative (compound 1) has been dissolved in dimethyl sulfoxide and added to the test sample (lymphoma or liver homogenate) in final concentrations of 1, 10 and 50 ƒÊM. The activities of superoxide dismutase and catalase have been determined spectrophotometrically in a homogenate of the lymphoma cells and homogenate of a liver (from both the grafted lymphoma and the healthy rats) after incubation with the drug for 10 minutes.
The baseline level of superoxide dismutase activity in the lymphoma of the rats has been 0.33 } 0.02 activity units/min~protein. Compound 1 significantly has increased the enzyme activity by 35% and 29% at concentrations of 10 and 50 ƒÊM, respectively. The baseline level of catalase activity has been 4.61 } 0.17 nmoles H2O2/min~mg protein and has significantly decreased by 15% with the action of the thiazole derivative at a concentration of 10 ƒÊM. The increase of superoxide dismutase activity in the case of decrease or absence of the changes in catalase activity have to be cytotoxic to cancer cells.
Since a liver is the main detoxification organ for most of drugs, including chemotherapeutic chemicals, hepatocytes have been selected in order to study the effects of substance 1 on healthy cells. It is known that the process of carcinogenesis not only causes the metastases in other organs (very often in a liver), but can also affect tissues in which metastases are not detected, that happens because of biologically active substances released by tumors to develop cancer. The state of the antioxidant defense system in normal liver of rats with grafted NK/Ly has been compared with the liver of the healthy rats without lymphoma. Superoxide dismutase activity have not differ in these two types of livers, while catalase activity has been drastically higher in the liver of rats with grafted lymphoma. The studied thiazole derivative has not affect the activity of the enzymes of the antioxidant system in the both type of livers.
In summary, the investigated thiazole derivative increases activity of superoxide dismutase in the lymphoma and does not affect the activity of the catalase (in doses 1 and 50 ƒÊM) or even reduces it (in 10 ƒÊM), that must increase the accumulation of H2O2 in the cancer cells. At the same time, compound 1 does not affect the activity of enzymes in the antioxidant system of the liver indicating the specificity of the action of this thiazole derivative in relation to cancer cells. Thus, these results show that cytotoxicity of newly synthetized thiazole derivative is related to the antioxidant system in lymphoma and can be used for further preclinical tests as a potential chemotherapeutic drug with the minimal effects on a liver.
Article recieved: 22.05.2018
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