Nevertheless, many clinical specialists are reluctant regarding the perspectives of anti-tumor therapies based exclusively on the heterocyclic compounds. Why so? First, in most cases, heterocyclic compounds have lower antitumor activity than classical chemotherapeutic agents do. Second, development of the new cytotoxic agents is an extremely cost-intensive process demanding milliards of dollars [5]. Taking into consideration the above, one can propose a new framework for the application of the heterocyclic compounds. The key idea of the framework is that heterocyclic compounds can possible used as adjuvants for the classical chemotherapy [6-9].

At the current stage, one cannot categorically assert the clinical efficacy of this approach. There are, however, several arguments supporting the idea. All chemotherapeutic agents have side effects. Their cytotoxic and cytostatic activity affects not only cancer, but also healthy tissues [10,11]. Despite all the efforts, these problems have no adequate solution so far. Moreover, apart from the cytotoxic action, chemotherapeutic agents can induce tolerance in some types of tumor cells [12,13]. One of the mechanisms underlying this tolerance is activation of Cyclin-Dependent Kinases (CDK). Fortunately, isothiazole derivatives effectively inhibit CDK8 and its paralog CDK19 [12], suppressing tumor cells proliferation [13-16]. This explains synergism, observed in the experiments with the combinations of heterocyclic compounds and classical chemotherapy. Isothiazoles in combination with chemotherapeutic agents provoked an intensive death of the tumor cells in vitro [6,8] and increased the survival rate in the animal tumor models [7,9].

In most cases, classical chemotherapy not only kills the tumor cells, but also stimulates gene expression in the damaged tissues, provoking synthesis of the tumor-supporting factors. It was found that phenotype of these factors results from the activation of CDK-interacting protein p21 (CDKN1A) [15]. Low-molecular compounds inhibiting p21 transcription were identified as selective inhibitors  of  the  CDK8  and  CDK19,  which  are  the  key player in the transcription process [13]. Interestingly, p21 binds CDK8 stimulating its kinase activity. CDK8 inhibitors suppress the paracrine activity of both – tumor cells and normal fibroblasts – promoting the adaptation of the tumor cells to the new conditions after chemotherapy [14]. Thus, CDK8, playing an important role in the processes of tumor epithelial–mesenchymal transition and invasion, represents an attractive target for the new anti-tumor therapies [16]. In general, tumor cells contain various targets, acting on which heterocyclic compounds can suppress the tumor cells proliferation.

CONCLUSION

Therefore, currently, there is a clear understanding of some mechanisms underlying the efficacy of the conjoint action of heterocyclic compounds and classical chemotherapeutic agents. This is further supported by the experimental results demonstrating that addition of the heterocyclic compounds allows decreasing the effective dose of chemotherapeutic agents by one or even two orders of magnitude [6-9,17]. Decrease of the cytostatic dose, in its turn, will reduce the side effects of the therapy [6-9,17] bonus that cannot be overemphasized. 

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