Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist.

Abstract

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.

• Authors: Luz E Tavera-Mendoza, Tan D Quach, Basel Dabbas, Jonathan Hudon, Xiaohong Liao, Ana Palijan, James L Gleason, John H White
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 24 Pg. 8250-5 (Jun 17 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18550844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytostatic Agents
• Cytotoxins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Receptors, Calcitriol
• triciferol
• trichostatin A
• Calcitriol

Topics

• Calcitriol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Calcium Signaling (drug effects)
• Cell Line, Tumor
• Cytostatic Agents (chemical synthesis, chemistry, pharmacology)
• Cytotoxins (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (chemistry)
• Molecular Structure
• Receptors, Calcitriol (agonists)