Title : PI3-Kinase inhibitors represent a novel class of drug repurposing candidates to prevent/ alleviate glucocorticoid-induced skin atrophy
Abstract:
S kin atrophy is a major adverse effect of topical glucocorticoids and is a serious clinical problem. We recently reported that several negative regulators of Akt/mTOR signaling including REDD1 (regulated in development and DNA damage 1) and FKBP5 (FK506 binding protein 5) are strongly induced by glucocorticoids in human and mouse skin, where they act as key drivers of steroid-induced atrophy. We hypothesized that REDD1 and Fkbp5 inhibitors may act as anti-atrophogenes, and could be used to protect tissues against catabolic effects of glucocorticoids. To search for anti-atrophogenes, we used the drug repurposing approach, and bioinformatically screened LINCS library (http://lincsproject.org/LINCS/) for repressors of REDD1 and FKBP51 expression. Unexpectedly, we identified phosphoinositide-3- kinase (PI3K)/mTOR/Akt inhibitors as a major pharmacological class of REDD1/FKBP51 repressors. We have chosen several PI3K/Akt/ mTOR inhibitors, including LY294002 and five others, and showed that all of them indeed blocked basal and glucocorticoid-induced REDD1 and FKBP51expression in human keratinocytes and in mouse skin. Further, PI3K/mTOR/Akt inhibitors modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted glucocorticoid receptor (GR) phosphorylation, nuclear translocation, and GR loading on REDD1 and FKBP51 gene promoters. Evermore, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test. These results built a foundation for development of safer GRtargeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors
