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 hematological 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, ~50% of top putative REDD1 inhibitors selected by bioinformatics screening of LINCS database 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 towards 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 inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that co-administration 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 hematological malignancies using PI3K/Akt/mTOR inhibitors.