Synergism of Vitamin D and Novel Rexinoids for the Prevention and Treatment of Major Human Diseases

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) as a heterodimer with RXR and associates with vitamin D-response elements (VDREs) to regulate transcription of target genes. Bexarotene (Bex) is an RXR ligand developed to treat cutaneous T-cell lymphoma and is a putative therapeutic for other diseases. We postulate that VDR ligands (vitamin D) and RXR ligands (Bex/analogs) can "synergize" to "super-activate" the VDR-RXR heterodimer. This "cross-talk" could allow disorders treated with high-dose Bex therapy (leading to significant adverse side-effects) to instead be treated using both low-dose Bex and vitamin D. Thus, we designed experiments to examine the effect of both VDR ligands (1,25D) and RXR ligands (Bex/analogs), alone and in combination, to activate VDR-RXR-mediated transcription. The assay system was composed of human kidney cells transfected with M2H or VDRE-luciferase reporter genes. The goal was to determine if select RXR-specific ligands can synergize with vitamin D to amplify RXR-VDR activity. The results demonstrate a synergistic effect with both Bex and vitamin D which could be further modulated by: 1) the protein levels (or polymorphic version) of VDR present in the cell, 2) the concentration of the ligands, 3) the cellular “background” (e.g., brain cells versus kidney cells), 4) the nature of the VDRE platform, or 5) the type of Bex analog. Our findings suggest that numerous diseases that respond to treatment with either vitamin D, or with rexinoids, may be amenable to enhanced therapeutic potential by employing multi-ligand dosing via combinatorial therapy.