Therapeutic Applications for Ligands of Retinoid Receptors

Abstract

Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARalpha and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama. RXR-specific retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications.

Active repression by RARγ signaling is required for vertebrate axial elongation

“…To separate the effects of RARγ in the posterior from RARα in the trunk, we characterized RARγ-selective agonist NRX204647 (4647) (Shimono et al, 2011;Thacher et al, 2000) and RARγ-selective inverse agonist NRX205099 (5099) (Tsang et al, 2003) in Xenopus embryos. Like AGN193109, 5099 is an inverse agonist, reducing RARγ signaling activity below basal levels by stabilizing the co-repressor complex bound to RARγ.…”

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

“…IFNs are used for treatment of several cancers, including RCC, in addition to viral and neurodegenerative diseases (Kalvakolanu et al, 2001;Cohen and McGovern, 2005). Retinoids are a class of vitamin A metabolites and/or synthetic derivatives, which are used for treatment of several cancers and other disorders (Thacher et al, 2000;Altucci and Gronemeyer, 2001). Previous studies from our lab and those of others showed that the IFN/RA combination synergistically suppresses tumor growth in pre-clinical and clinical settings, compared to the individual agents (Moore et al, 1994;Kalvakolanu, 2004).…”

Retinoic acid induces PGI synthase expression in human endothelial cells

“…Natural and synthetic derivatives of vitamin A (retinoids) exert profound effects on growth, maturation, and differentiation of many cell types (14), and are currently used in cancer and several dermatological disease therapies (15,16). Retinoids also exhibit putatively beneficial biological actions in the cardiovascular system.…”