Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor.

Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis.

Differential effects of PPARgamma ligands on oxidative stress-induced death of retinal pigmented epithelial cells.

Purpose: To investigate the role of the peroxisome proliferator-activated receptor (PPAR)-γ in modulating retinal pigmented epithelium (RPE) responses to oxidative stress.

Methods: ARPE-19 cells were treated with the oxidant, t-butylhydroperoxide (tBH) to induce apoptosis. Cells pretreated with synthetic PPARγ agonists of the antidiabetic thiazolidinediones class before tBH challenge were assessed for viability and, by microarray analysis, for effects on gene expression.

Retinoid-related molecule AGN193198 potently induces G2M arrest and apoptosis in bladder cancer cells.

The novel synthetic retinoid-related molecule 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-propenyl]benzoic acid (AGN193198) neither binds effectively to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) nor transactivates in RAR- and RXR-mediated reporter assays. Even so, AGN193198 is potent in inducing apoptosis in human prostate and breast carcinoma cells (Keedwell et al., Cancer Res 2004;64:3302-12).

A retinoid-related molecule that does not bind to classical retinoid receptors potently induces apoptosis in human prostate cancer cells through rapid caspase activation.

Synthetic retinoid-related molecules, such as N-(4-hydroxyphenyl)retinamide (fenretinide) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induce apoptosis in a variety of malignant cells. The mechanism(s) of action of these compounds does not appear to involve retinoic acid receptors (RARs) and retinoid X receptors (RXRs), although some investigators disagree with this view. To clarify whether some retinoid-related molecules can induce apoptosis without involving RARs and/or RXRs, we used 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-E-propenyl] benzoic acid (AGN193198) that neither binds effectively to RARs and RXRs nor transactivates in RAR- and RXR-mediated reporter assays.