Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist.
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.
Departments of Medicine and Physiology, McIntyre Building, McGill University, 3655 Drummond Street, Montreal, QC, Canada.
Luz E
LE
Tavera-Mendoza
Tan D
TD
Quach
Basel
B
Dabbas
Jonathan
J
Hudon
Xiaohong
X
Liao
Ana
A
Palijan
James L
JL
Gleason
John H
JH
White
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000819:agonists*
D054697:Cytostatic Agents; D003603:Cytotoxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018167:Receptors, Calcitriol; C530068:triciferol; C012589:trichostatin A; D002117:Calcitriol