Graduate Student Arizona State University Phoenix, Arizona, United States
Sabeeha Mushtaq Reshi (Arizona State University)| Sanchita Mallick (Arizona State University)| Pamela Marshall (Arizona State University)| Carl Wagner (Arizona State University)| Peter Jurutka (Arizona State University, University of Arizona College of Medicine)
Bexarotene is a synthetic rexinoid that binds to the retinoid X receptor (RXR) causing a signaling cascade that results in transcription of RXR target genes to control cellular differentiation, apoptosis, and proliferation. Bexarotene is an FDA-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL) and non-small cell lung cancer. Off-label use has been extended to breast cancer, although significant side effects like hyperlipidemia and hypothyroidism can occur because bexarotene not only modulates retinoid-X-response element (RXRE)-regulated transcription but it also acts as an RXR heterodimer-selective agonist resulting in activation of other RXR-containing heterodimers. Bexarotene has also shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid-β in transgenic mice expressing familial Alzheimer’s disease mutations. The RXR heterodimers with the liver‐X‐receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARγ) control cholesterol efflux, inflammation, and transcriptionally regulate the production of apolipoprotein (ApoE) in the brain. In the present study, we assessed the potential of bexarotene and a group of novel rexinoids to induce RXR dimerization using a mammalian two-hybrid system (M2H). RXRE-mediated reporter assays were also employed to assess the transcriptional efficiency of these compounds. LXRE-mediated luciferase assays were performed to analyze the role of the novel compounds as activators of LXRE‐directed transcription, and as inducers of ApoE mRNA in U87 glial cells. Results from these multiple assays indicate that our panel of RXR analogs contain compounds with an assortment of activities, some of which bind to RXR with higher affinity than others, and in some cases can upregulate ApoE expression to a greater extent than bexarotene. These results suggest that minor modifications to the bexarotene core chemical structure may yield more potent novel analogs which allows for their therapeutic use at lower concentrations, thereby potentially reducing the corresponding side effects associated with high-dose bexarotene therapy. Moreover, these results indicate that some of the novel analogs possess a greater capacity to activate RXR and may be useful as therapeutic agents against both cancers as well as neurodegenerative disorders including Alzheimer’s disease.