Introduction. Glucocorticoids are the important component of combined chemotherapy of blood cancer. Therapeutic effects of glucocorticoids is realized via activation of glucocorticoid receptor transrepression, the development of side effects is associated with transactivation. We demonstrated earlier that compound belonging the class of selective glucocorticoid receptor agonists, CpdA, selectively induced transrepression in blood cancer cells. CpdA represents a mixture of two enantiomers, which can differ in interaction with the receptor. Aim. The main aim of present study was to synthesize CpdA enantiomers and to evaluate their biological properties. Materials and methods. Synthesis was carried out based on Sharpless dihydroxylation; anti-tumor activity in vitro was evaluated by antiproliferative and pro-apoptotic effects. Ligand properties were estimated by PCR-analysis of glucocorticoid- and NF-kB-dependent genes expression. Results and conclusions. We demonstrated that CpdA enantiomers revealed anti-tumor activity in vitro and did not induce transactivation. Moreover, S-enantiomer of CpdA in the most tests demonstrated more pronounced activity and is more perspective molecule for future studies in vivo.
Hematological disorders include a wide spectrum of malignancies of hematopoietic and lymphoid tissues. The genetic changes underlying the pathogenesis of the diseases are specific for each disease. High incidence of chromosomal aberrations (deletion, translocation, insertion) is one of the principal characteristics of oncohematological diseases. In addition, mutations in individual genes or blocking of normal regulation of gene functioning in relation to epigenetic events can occur. Progression of oncohematological diseases could be a result of accumulation of different genetic abnormalities. Modern classification of malignancies of hematopoietic and lymphoid tissues is based on the analysis of clinical data, morphological and functional characteristics of tumor cells and identification of specific cytogenetic and molecular-genetic changes. A large number of genetic abnormalities specific for certain types of hematological malignancies has been discovered to date. It allows to optimize the treatment strategy, as well as to design, test and introduce to the clinical practice a number of targeted drugs (inhibitors of chimeric proteins formed as a result of trans-locations and triggering the malignant cell transformation). Drugs based on monoclonal antibodies (Rituximab, Alemtuzumab, etc.) or low molecular weight compounds (Imatinib, Bortezomib, Carfilzomib) form this group of medications. The knowledge about not only specific gene abnormalities but also about the corresponding changes in cell efferent signaling pathways could be of great interest for the development of new targeted molecules or the repurposing of known chemotherapeutic agents. The present review compares genetic aberrations in diseases listed in the 2008 WHO classification (amended in 2016) of hematopoietic and lymphoid tissue malignancies and main changes in cell signaling pathways associated with malignant transformation of hematopoietic cells.
IntroductionGlucocorticoids (GCs) are widely used in blood cancer treatment; although, they cause metabolic disorders. Biological response to GCs is mediated by glucocorticoid receptor (GR) regulating gene expression via transactivation (TA), which requires GR binding to GC-responsive elements in gene promoters, and transrepression (TR), negative interaction between GR and transcription factors. TR mediates anticancer effects of GR, while side effects are associated with GR TA. Selective GR agonists (SEGRAs) that preferentially activate GR TR could be a better option for cancer treatment. One of well characterised SEGRAs is 2-(4-acetoxyphenyl)−2-chloro-N-methylethylammonium-chloride, or CpdA, isolated from Namibian shrub Salsola tuberculatiformis. CpdA demonstrated anticancer activity in vitro and in vivo. We extended SEGRA list by synthesis of CpdA enantiomers and its chemical derivatives.Material and methodsSynthesis of (S) and (R)-CpdA was based on Sharpless asymmetric dihydroxylation. Chemical analogues of CpdA, CpdA01-08, were designed by appending of bulky substituent into benzene ring and to nitrogen atom or alkylation of carbon atom adjacent to chlorine atom. All experiments in vitro were carried out on Granta (lymphoma) and CEM (leukaemia) cells. Cells were treated with Dex, CpdA, (R) and (S)-CpdA, CpdA01-08. Effects on cell growth were evaluated by cell counting and flow cytometry. Affinity to GR was measured by competitive binding assay. Gene expression was measured by qPCR and Western blotting. GR and NF-kB activity was evaluated using Luciferase reporter analysis. Anticancer effect in vivo was determined using the model of murine lymphoma P388.Results and discussionsThe most cytotoxic compounds among 10 newly synthesised, CpdA03 and CpdA05, demonstrated the highest affinity to GR. They induced GR TR but not TA and proved their SEGRA properties. Effect of CpdA enantiomers on cell growth and survival was not significantly different from Dex and CpdA. CpdA03, cytotoxic SEGRA with the highest affinity to GR, comparable with DEX and CpdA, was tested in vivo for evaluation its anti-lymphoma activity, and demonstrated 3-fold decrease of tumour size in comparison with 2–2,5-fold decrease after Dex or CpdA treatment.ConclusionThe design of synthesis and evaluation of anticancer properties of new SEGRA are provided. According to our data one novel SEGRA, CpdA03, is perspective for further investigation as anti-lymphoma drug with reduced side effects.Study is funded by Russian Science Foundation No. 17-75-20124.
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