Regulated in Development and DNA Damage Response 1 (REDD1)/DNA Damage-Induced Transcript 4 (DDIT4) is an immediate early response gene activated by different stress conditions, including growth factor depletion, hypoxia, DNA damage, and stress hormones, i.e., glucocorticoids. The most known functions of REDD1 are the inhibition of proliferative signaling and the regulation of metabolism via the repression of the central regulator of these processes, the mammalian target of rapamycin (mTOR). The involvement of REDD1 in cell growth, apoptosis, metabolism, and oxidative stress implies its role in various pathological conditions, including cancer and inflammatory diseases. Recently, REDD1 was identified as one of the central genes mechanistically involved in undesirable atrophic effects induced by chronic topical and systemic glucocorticoids widely used for the treatment of blood cancer and inflammatory diseases. In this review, we discuss the role of REDD1 in the regulation of cell signaling and processes in normal and cancer cells, its involvement in the pathogenesis of different diseases, and the approach to safer glucocorticoid receptor (GR)-targeted therapies via a combination of glucocorticoids and REDD1 inhibitors to decrease the adverse atrophogenic effects of these steroids.

Introduction. Glucocorticoids (GC) are widely used in breast cancer (BC) therapy to reduce the side effects of cytostatic drugs and may exhibit antiproliferative effects on luminal BC cells. The biological action of GC is mediated by glucocorticoid receptor (GR) by two mechanisms: transrepression, which determines the therapeutic effect of GC, and transactivation (associated with the development of side effects, resistance to cytotoxic drugs, cancer progression and metastasis). Selective GR agonists (SEGRA) which may selective activate transrepression are a promising alternative to GC to use in combination cancer therapy. One of the most studied SEGRA is Compound A (CpdA). The instability of CpdA limits its use in clinical practice. So recently we performed synthesis and evaluation of biological activities of the CpdA analogue, CpdA-03.Aim. To compare the effects of SEGRA CpdA-03 and CpdA and dexamethasone on proliferative activity of breast cancer cells, as well as receptor nuclear translocation and activation of GR-dependent genes in breast cancer cells.Materials and methods. Luminal (MCF-7) and triple negative (MDA-MB-231) BC cell lines were used. The effect of CpdA-03 on proliferation was evaluated by direct counting of viable cells with trypan blue staining. The effect of the compound on cell distribution by cell cycle phases was assessed by flow cytofluorimetry with propidium iodide staining. Changes in the expression of GR-dependent genes after incubation with CpdA-03 were evaluated by quantitative polymerase chain reaction. Additionally, the ability of the new SEGRA to induce transactivation-associated translocation of the receptor to the nucleus was evaluated by Western blotting.Results. CpdA-03 was shown to suppress proliferation of luminal and triple negative BC cells. This compound causes changes in the expression of a number of GC-inducible genes, but does not stimulate GR phosphorylation and translocation to the nucleus in BC cells.Conclusion. The observed suppression of cell proliferation, as well as the ability of CpdA-03 to reduce gene expression of proteins regulating intercellular adhesion and cell migration, intracellular signaling, stress response, and transcription in BC cells makes it relevant for further development of the drug for use in the combination therapy of cancers including breast cancer.

Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs have been described so far, yet none of them reached clinical trials for anti-cancer treatment. In the present work, we propose a novel approach to increase the number of potential SEGRAs by obtaining derivatives of synephrine, a molecule of natural origin. We synthesized 26 novel compounds from the class of synephrine derivatives and characterized them by HRMS, and ¹H and ¹³C NMR. We evaluated in vitro anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) in silico using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico exhibited cytotoxic activity against K562 and Granta cells after 24 h of treatment at the concentration of approximately 13 µM which correlated with its highest MolDock Score. The other compound with high GR affinity, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2), demonstrated cytotoxicity in both cell lines at concentrations of 50–70 µM. Overall, our results may provide a solid rationale for developing and further investigating synephrine derivatives as SEGRAs with anti-cancer activity.

Glucocorticoids (GC) are widely used in the treatment of hematological malignancies; however, the long-term treatment lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRA) with reduced side effects could be the better GC alternative. More than 30 SEGRA were described but none of them reached clinical trials as anticancer treatment. In the present work, we proposed the novel approach to broaden the list of potential SEGRA by synthesis of derivatives of synephrine, the molecule of natural origin. We synthesized 26 compounds from the class of synephrine derivatives, and studied their anticancer effect in vitro in leukemia and lymphoma cells with MTT assay as well as their potential affinity to glucocorticoid receptor (GR) in silico using molecular docking approach. Novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico revealed the micromolar range cytotoxicity in lymphoma and leukemia cells after 24 h of treatment. The other compound, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2) with high GR affinity demonstrated cytotoxicity in the range of 50-70 µM. Overall, our results provide the rationale for the development and further investigation of synephrine derivatives as SEGRA with anticancer activity.

Objective: screening of previously selected DDIT4 inhibitors by their ability to suppress basal and glucocorticoid-induced expression of this gene in breast cancer (BC) cells, as well as evaluation of antiproliferative and cytotoxic effects of the studied drug combinations the antiproliferative and proapoptotic effects of studied drug combinations. Material and Methods. Breast cancer cells of the luminal, HER2- positive and triple negative subtypes were used. The effects of drugs (rapamycin, wortmannin, LY-294002, apigenin, resveratrol, curcumin, CGP-60474, and emetine) on the basal and glucocorticoid-induced levels of expression of the DDIT4 gene and its protein product were evaluated by qPCR and Western blotting assays. Results. Emetine, rapamycin, wortmannin, LY-294002 and CGP-60474 demonstrated DDIT4-inhibition activity. Glucocorticoid dexamethasone showed cytotoxic effects and antiproliferative activity in combination with emetine, CGP-60474 (C protein kinase inhibitor), resveratrol and curcumin. Conclusion. Novel inhibitors of DDIT4 in breast cancer model cells in vitro were found. Emetine and CGP-60474 are the most promising drugs for further research.

Introduction. Current chemotherapy of breast cancer has a wide range of disadvantages, in particular, the development of therapy-related infections and hormonal imbalance. Combination of main cytostatic with glucocorticoids allows to broaden its therapeutic interval and to decrease the total toxicity of the treatment. However, long-term treatment with glucocorticoids leads to the development of severe side effects via activation of multiple molecular mechanisms. Thus, glucocorticoids activate prosurvival mTOR-dependent autophagy. Therefore, the evaluation of PI3K (phosphoinositide 3-kinases) / Akt (protein kinase B) / mTOR (mammalian target of rapamycin) inhibitors as adjuvants for breast cancer therapy is important for optimization of treatment protocol.Aim. Analysis of the effects of PI3K/Akt/mTOR inhibitors, rapamycin, wortmannin and LY-294002 in combination with glucocorticoids in breast cancer cell lines of different subtypes.Materials and methods. We demonstrated the inhibition of PI3K/Akt/mTOR signaling and the autophagy induction after the treatment of breast cancer cells with rapamycin, wortmannin and LY-294002 by Western blotting analysis of Beclin-1, phospho-Beclin-1 (Ser93 and Ser30).Conclusion. PI3K/Akt/mTOR inhibitors in combination with Dexamethasone cooperatively inhibited mTOR signaling and activated autophagy in breast cancer cells in vitro.