Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/ mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/ mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitorþDexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.

Glucocorticoids (GCs) are stress hormones that play multiple roles in the regulation of cancer cell differentiation, apoptosis, and proliferation. Some types of cancers, such as hematological malignancies, can be effectively treated by GCs, whereas the responses of epithelial cancers to GC treatment vary, even within cancer subtypes. In particular, GCs are frequently used as supporting treatment of breast cancer (BC) to protect against chemotherapy side effects. In the therapy of nonaggressive luminal subtypes of BC, GCs can have auxiliary antitumor effects due to their cytotoxic actions on cancer cells. However, GCs can promote BC progression, colonization of distant metastatic sites, and metastasis. The effects of GCs on cell proliferation vary with BC subtype and its molecular profile and are realized via the activation of glucocorticoid receptor (GR), a well-known transcriptional factor involved in the regulation of the expression of multiple genes, cell-cell adhesion, and cell migration and polarity. This review focuses on the roles of GC signaling in the adhesion, migration, and metastasis of BC cells. We discuss the molecular mechanisms of GC actions that lead to BC metastasis and propose alternative pharmacological uses of GCs for BC treatment.

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.

Glucocorticoids (Gcs) are widely used to treat inflammatory diseases and hematological malignancies, and despite the introduction of novel anti-inflammatory and anti-cancer biologics, the use of inexpensive and effective Gcs is expected to grow. Unfortunately, chronic treatment with Gcs results in multiple atrophic and metabolic side effects. Thus, the search for safer glucocorticoid receptor (GR)-targeted therapies that preserve therapeutic potential of Gcs but result in fewer adverse effects remains highly relevant. Development of selective GR agonists/modulators (SEGRAM) with reduced side effects, based on the concept of dissociation of GR transactivation and transrepression functions, resulted in limited success, and currently focus has shifted towards partial GR agonists. Additional approach is the identification and inhibition of genes associated with Gcs specific side effects. Others and we recently identified GR target genes REDD1 and FKBP51 as key mediators of Gcs-induced atrophy, and selected and validated candidate molecules for REDD1 blockage including PI3K/Akt/mTOR inhibitors. In this review, we summarized classic and contemporary approaches to safer GR-mediated therapies including unique concept of Gcs combination with REDD1 inhibitors. We discussed protective effects of REDD1 inhibitors against Gcs–induced atrophy in skin and bone and underlined the translational potential of this combination for further development of safer and effective Gcs-based therapies.

Safe and healthy nutrition has a beneficial effect on human well-being. Various foods, such as berries, are known to inhibit cancer-promoting pre-proliferative signals. Among European fruit and berry crops, raspberries demonstrate one with the widest ranges of biologically active substances. Extraction remains a reliable method of obtaining biologically active substances from plant materials. The research objective was to obtain a semi-finished raspberry product by using microwave and ultrasonic processing and to study its antioxidant, anti-carcinogenic, sensory, physico-chemical, and microbiological properties. The raspberry extracts were obtained by maceration, ultrasound treatment, and microwave processing. After that, the samples underwent a comparative analysis of their antioxidant properties. The ultrasonic method gave the best results. A set of experiments made it possible to define the optimal technological modes for the extraction process: ethanol = 50%, ultrasonic radiation = 35 kHz, temperature = 40 ± 5°C, time = 120 min, water ratio = 1:10. A set of experiments on cell cultures demonstrated that the raspberry extract was able to reduce the expression of the anti-inflammatory COX-2, iNOS, and IL-8 genes. Hense, we recommend further studies of the effect of the raspberry extract on the induced expression of COX-2, iNOS, and IL-8. In addition, its anticarcinogenic properties have to be studied in vivo.