Oncotarget

Reviews:

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

Ekaterina A. Lesovaya _, Daria Chudakova, Gleb Baida, Ekaterina M. Zhidkova, Kirill I. Kirsanov, Marianna G. Yakubovskaya and Irina V. Budunova

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Abstract

Ekaterina A. Lesovaya1,2, Daria Chudakova3, Gleb Baida3, Ekaterina M. Zhidkova1, Kirill I. Kirsanov1,4, Marianna G. Yakubovskaya1 and Irina V. Budunova3

1 Deparment of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin NMRCO, Moscow, Russia

2 Department of Oncology, I.P. Pavlov Ryazan State Medical University, Ryazan, Russia

3 Department of Dermatology, Northwestern University, Chicago, IL, USA

4 Deparment of General Medical Practice, RUDN University, Moscow, Russia

Correspondence to:

Ekaterina A. Lesovaya, email: lesovenok@yandex.ru

Keywords: glucocorticoid receptor; glucocorticoids; SEGRAM; REDD1; drug repurposing

Received: December 13, 2021     Accepted: January 25, 2022     Published: February 18, 2022

Copyright: © 2022 Lesovaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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.


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