School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA.
Cells. 2024 Nov 14;13(22):1878. doi: 10.3390/cells13221878.
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) with high affinity. The VDR then heterodimerizes with the retinoid X receptor (RXR) and associates with vitamin D response elements (VDREs) to regulate the transcription of target genes. Bexarotene (Bex) is an RXR ligand (rexinoid) developed to treat cutaneous T-cell lymphoma and is a putative therapeutic for other diseases. We postulate that VDR ligands (1,25D) 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 and RXR ligands, alone and in combination, to activate VDR-RXR-mediated transcription. The goal was to determine if selected RXR-specific ligands can synergize with vitamin D to amplify RXR-VDR activity. The results demonstrate a synergistic effect with both Bex and 1,25D 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 rexinoid (Bex analogs). Our findings suggest that 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.
维生素 D 的活性形式，1,25-二羟维生素 D（1,25D），与维生素 D 受体（VDR）高亲和力结合。然后 VDR 与维甲酸 X 受体（RXR）异二聚化，并与维生素 D 反应元件（VDREs）结合，以调节靶基因的转录。贝沙罗汀（Bex）是一种 RXR 配体（类视黄醇），开发用于治疗皮肤 T 细胞淋巴瘤，并且是其他疾病的潜在治疗药物。我们假设 VDR 配体（1,25D）和 RXR 配体（Bex/类似物）可以“协同作用”以“超激活”VDR-RXR 异二聚体。这种“串扰”可以使使用高剂量 Bex 治疗（导致显著不良反应）的疾病改为使用低剂量 Bex 和维生素 D 治疗。因此，我们设计了实验来研究单独和组合使用 VDR 和 RXR 配体对激活 VDR-RXR 介导的转录的影响。目标是确定选定的 RXR 特异性配体是否可以与维生素 D 协同作用以放大 RXR-VDR 活性。结果表明，Bex 和 1,25D 均具有协同作用，并且可以通过以下方式进一步调节：（1）细胞中存在的 VDR 的蛋白水平（或多态性版本），（2）配体的浓度，（3）细胞“背景”（例如，脑细胞与肾细胞），（4）VDRE 平台的性质，或（5）类视黄醇（Bex 类似物）的类型。我们的发现表明，对维生素 D 或类视黄醇治疗有反应的疾病可能通过组合治疗采用多配体给药来增强治疗潜力。
