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 are often used in combination therapy for breast cancer as an adjuvant to increase therapeutic effects of the main cytotoxic drug and to reduce side effects of chemotherapy. However, glucocorticoids can cause serious complications and trigger tumor progression. In the last decade, it was found that side effects from glucocorticoids are mediated by an increase in REDD1 gene expression. Using this knowledge, we have developed a new chemotherapeutic strategy for blood cancers aimed at reducing adverse events from glucocorticoids. Successful experiments with a combination of glucocorticoids and REDD1 expression inhibitors on the models of blood tumors allowed us to use this regimen for the treatment of certain subtypes of breast cancer.Objective: to optimize the algorithm of breast cancer cell treatment with a combination of glucocorticoids and REDD1 expression inhibitors on the example of rapamycin.Materials and methods. We used the MCF-7 and MDA-MB-231 breast cancer cell lines. The antiproliferative activity was estimated by direct cell count; REDD1 expression was measured using western blotting and quantitative polymerase chain reaction.Results. We found that rapamycin can inhibit both baseline and glucocorticoids induced REDD1 expression in the cells of luminal and triple negative breast cancer. The drug demonstrated lower ability to inhibit the viability of breast cancer cells than that of leukemia and lymphoma cells.Conclusion. Inhibited proliferation of breast cancer cells after their incubation with rapamycin and dexamethasone, as well as the ability of rapamycin to reduce basal and glucocorticoid-induced REDD1 expression in breast cancer cells suggest the importance of studies analyzing the impact of combinations that include glucocorticoids and REDD1 expression inhibitors from the class of PI3K/Akt/mTOR signaling pathway modulators (phosphoinositide-3-kinase/α-serine-threonine kinase/mammalian rapamycin target) on breast cancer cells.

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.

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.