Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

Anna Klopot; Gleb Baida; Pankaj Bhalla; Guy Haegeman; Irina Budunova

추천

검색

자료유형: 학술저널

저자정보: Anna Klopot (Northwestern University Chicago IL USA) Gleb Baida (Gleb Baida) Pankaj Bhalla (Northwestern University Chicago IL USA) Guy Haegeman (Chulalonkorn University Bangkok Thailand) Irina Budunova (Northwestern University Chicago IL USA)

저널정보: 대한암예방학회 대한암예방학회지 대한암예방학회지 제20권 제4호

발행연도: 2015.1

수록면: 250 - 259 (10page)

이용수

📌

연구주제

📖

연구배경

🔬

연구방법

🏆

연구결과

초록· 키워드

오류제보하기

Background: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes. Methods: We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA. Results: In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy. Conclusions: Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.

참고문헌 (49)

참고문헌 신청

Lesovaya E / 2015 / Discovery of compound A: a selective activator of the glucocorticoid receptor with anti-inflammatory and anti-cancer activity / Oncotarget 6:30730~30744

Chebotaev D / 2007 / The mechanisms of tumor suppressor effect of glucocorticoid receptor in skin / Mol Carcinog 46:732~740

Schoepe S / 2006 / Glucocorticoid therapy-induced skin atrophy / Exp Dermatol 15:406~420

Schäcke H / 2006 / Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index / Exp Dermatol 15:565~573

Schoepe S / 2010 / Identification of novel in vitro test systems for the determination of glucocorticoid receptor ligand-induced skin atrophy / Skin Pharmacol Physiol 23:139~151

함께 읽어보면 좋을 논문

논문 유사도에 따라 DBpia 가 추천하는 논문입니다. 함께 보면 좋을 연관 논문을 확인해보세요!