A Novel Approach to Safer Glucocorticoid Receptor–Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition

Abstract

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.

mTOR Signaling Components in Tumor Mechanobiology

“…mTOR pathway either participates in force-induced molecular mechanisms that confer resistance to applied treatment or mTOR targeting holds promise for cancer cells' resensitization to chemotherapy, targeted therapy, or radiotherapy. Thereby, future studies should further investigate the interplay between mTOR signaling and mechanotransduction but also focus on elucidating the role of this central hub in mechanisms of drug resistance and the results of mTOR combination treatments [121,122].…”

The long winding road to the safer glucocorticoid receptor (GR) targeting therapies

“…Later this approach was extended towards osteoporosis model. We used the model of Gc-induced osteoporosis in mice and demonstrated the potency of PI3K/Akt/mTOR modulators to diminish bone resorption induced by Dex [ 150 ].…”

“…The computational screening of LINCS database of ~ 20,000 transcriptional signatures induced by FDA-approved and experimental drugs ( http://lincsproject.org/LINCS/ ) identified a significant number of putative inhibitors of REDD1 expression among pharmacological class of PI3K/Akt/mTOR inhibitors [ 150 , 154 , 157 ] including classical experimental inhibitors such as LY294002 and Wortmannin (WM), and drugs in clinic/clinical trials such as Rapamycin (Rapa) and AZD8055 ( Figure 1 ). This was completely unexpected as PI3K/Akt/mTOR inhibitors block major pro-proliferative signaling in cells.…”

“…The expression of REDD1 was determined by Western blotting and Q-PCR and normalized to Rpl27 expression. References: [ 150 , 154 ]. Abbreviation: N/A: not assessed.…”

“…Further, we demonstrated that combination of Gcs with PI3K inhibitors did not affect anti-inflammatory activity of Gcs in croton oil ear edema test [ 124 , 133 ]. Moreover, Rapamycin and LY294002 enhanced anti-lymphoma effects of Dex in human lymphoma xenograft model, and the therapeutic effects of PI3K inhibitor + Dex combinations ranged from cooperative to synergistic compared to single treatment [ 150 ].…”