Сhemotherapy is one of the most effective ways of treating patients with oncologic diseases, however, its application is accompanied by frequent non-addressed action leading to numerous negative side effects. Thus, new drugs should be developed. Besides, drug carriers are created in order to overcome drug-resistance mechanisms and provide addressed action in the organism. We have synthesized novel 4-thiazolidinone derivatives (compounds ID 3288, ID 3833, ID 3882) of potential anticancer activity, and demonstrated their effectiveness during treatment of tumor cells in vitro. Their antineoplastic action towards 60 human tumor cell lines was studied at the National Cancer Institute (Bethesda, USA). However, the mechanisms of functioning of these compounds in vivo, as well as their potential negative side effects (cardio-, hepato- and nephrotoxicity) were not known, and, thus, were the goal of the present study. Since the therapeutic effect of most anticancer drugs is strongly dependent on a balance of free radical oxidation and antioxidant activity. We addressed identifying possible ways of deregulation of metabolic parameters in rat serum and naturally detoxifying action of new derivatives of 4-thiazolidinone. A correlation between the main indicators of free radical oxidation as criteria for a degree of damaging effects in rats of new synthetic 4-thiazolidinone derivatives (compounds ID 3288, ID 3833, ID 3882) and their antineoplastic activity, compared with the effect of known anticancer drug doxorubicin used as a positive control, was analyzed. The ways of generation and functions of free radical oxygen metabolites in the body of experimental animals exposed to these derivatives are discussed. Our studies show that the redox balance of the cells required to maintain steady levels of the reactive oxygen species (ROS) are most informative for the study of mechanisms of action of highly toxic anticancer factors. The results of in vivo experiments for the action of experimental anticancer drugs demonstrated changes in the concentration of free radical oxidation of metabolites in blood serum of laboratory rats. It was established that ID 3833, similar to doxorubicin, enhanced the oxidative stress and generation of the ROS, while the action ID 3288 and ID 3882 did not lead to a significant activation of free radical oxidation.

Big attention was paid to the mechanisms of interference between chemotherapy and induced production of ROS. It was shown that 4-thiazolidinone derivatives under study possessed considerably lower general toxicity than doxorubicin. These results are consistent with the cytotoxic investigation of anticancer derivatives showing the highest pro-apoptotic effect of ID 3288 on rat glioma C6 cell line and the absence of such action of ID 3882, while doxorubicin and ID 3833 demonstrated intermediate degree on toxic effects towards these cells. A statistical correlation analysis and determination of the correlation coefficient (r) between the biochemical indicators for the actions of each of the antitumor compound in vivo and in-vitro were done. The obtained results suggest different mechanism(s) of cytotoxic action of anticancer compounds involving inhibition or activation of free radical oxidation (FRO). For the action of ID 3882, there was no close correlation found between the cytotoxic effect and concentration of metabolites of FRO that might indicate a weak effect of this drug on rat C6 glioma cells. It is concluded about the importance of maintaining a balance of free radical processes that should be taken into account when developing new anticancer drugs. At the creation of new drugs for anticancer therapy, it is important to determine redox balance and intensity of FRO at the cellular and systemic levels. These indicators can serve as important biomarkers to evaluate the efficacy and toxicity of traditional and innovative anticancer drugs.

This will not only provide a good therapeutic action but also reduce their negative side effects in the organism.

Article Received 17.06.2016

Ключові слова: 4-thiazolidinones, doxorubicin, free radical oxidation, reactive oxygen species, correlation analysis

Повний текст: PDF (Ukr)

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