Tavera-Mendoza Luz E, Quach Tan D, Dabbas Basel, Hudon Jonathan, Liao Xiaohong, Palijan Ana, Gleason James L, White John H
Departments of Medicine and Physiology, McIntyre Building, McGill University, 3655 Drummond Street, Montreal, QC, Canada.
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8250-5. doi: 10.1073/pnas.0709279105. Epub 2008 Jun 12.
1,25-dihydroxyvitamin D(3) (1,25D) regulates gene expression by signaling through the nuclear vitamin D receptor (VDR) transcription factor and exhibits calcium homeostatic, anticancer, and immunomodulatory properties. Histone deacetylase inhibitors (HDACis) alter nuclear and cytoplasmic protein acetylation, modify gene expression, and have potential for treatment of cancer and other indications. The function of nuclear receptor ligands, including 1,25D, can be enhanced in combination with HDACi. We designed triciferol, a hybrid molecule in which the 1,25D side chain was replaced with the dienyl hydroxamic acid of HDACi trichostatin A. Triciferol binds directly to the VDR, and functions as an agonist with 1,25D-like potency on several 1,25D target genes. Moreover, unlike 1,25D, triciferol induces marked tubulin hyperacetylation, and augments histone acetylation at concentrations that largely overlap those where VDR agonism is observed. Triciferol also exhibits more efficacious antiproliferative and cytotoxic activities than 1,25D in four cancer cell models in vitro. The bifunctionality of triciferol is notable because (i) the HDACi activity is generated by modifying the 1,25D side chain without resorting to linker technology and (ii) 1,25D and HDACi have sympathetic, but very distinct biochemical targets; the hydrophobic VDR ligand binding domain and the active sites of HDACs, which are zinc metalloenzymes. These studies demonstrate the feasibility of combining HDAC inhibition with nuclear receptor agonism to enhance their therapeutic potential.
1,25 - 二羟基维生素D(3)（1,25D）通过核维生素D受体（VDR）转录因子进行信号传导来调节基因表达，并具有钙稳态、抗癌和免疫调节特性。组蛋白去乙酰化酶抑制剂（HDACis）可改变细胞核和细胞质蛋白的乙酰化状态，修饰基因表达，具有治疗癌症和其他疾病的潜力。包括1,25D在内的核受体配体的功能可与HDACi联合增强。我们设计了三烯醇，这是一种杂合分子，其中1,25D的侧链被HDACi曲古抑菌素A的二烯基异羟肟酸取代。三烯醇直接与VDR结合，并作为一种激动剂，对多个1,25D靶基因具有类似1,25D的活性。此外，与1,25D不同，三烯醇可诱导明显的微管蛋白超乙酰化，并在与观察到VDR激动作用的浓度大致重叠的浓度下增强组蛋白乙酰化。在四种体外癌细胞模型中，三烯醇还表现出比1,25D更有效的抗增殖和细胞毒性活性。三烯醇的双功能性值得注意，因为（i）HDACi活性是通过修饰1,25D侧链产生的，无需借助连接技术；（ii）1,25D和HDACi具有相似但非常不同的生化靶点，即疏水性的VDR配体结合结构域和HDACs的活性位点，HDACs是锌金属酶。这些研究证明了将HDAC抑制与核受体激动作用相结合以增强其治疗潜力的可行性。
