title: The tricyclic antidepressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases: in vitro and in silico evidence.
abstract: Amitriptyline is a classic tricyclic antidepressant (TCA) and has been used to treat the depression and anxiety of patients with cancer, but its relevance to cancer cell apoptosis is not known. In the present study, we demonstrated that amitriptyline inhibited cyclin D2 transactivation and displayed potential antimyeloma activity by inhibiting histone deacetylases (HDACs). Amitriptyline markedly decreased cyclin D2 promoter-driven luciferase activity, reduced cyclin D2 expression, and arrested cells at the G(0)/G(1) phase of the cell cycle. Amitriptyline-induced apoptosis was confirmed by Annexin V staining, and cleavage of caspase-3 and poly(ADP-ribose) polymerase-1. D-Cyclin expression is reported to be epigenetically regulated by histone acetylation. Thus, we examined the effects of amitriptyline on histone 3 (H3) acetylation and demonstrated that amitriptyline increased acetylation of H3 and expression of p27 and p21. Further studies indicated that amitriptyline interfered with HDAC function by down-regulation of HDAC3, -6, -7, and -8, but not HDAC2, and by interacting with HDAC7. Molecular docking analysis and molecular dynamics simulations revealed that amitriptyline bound to HDAC7 and formed strong van der Waals interactions with five residues of HDAC7, including Phe162, His192, Phe221, Leu293, and His326, thus inhibiting HDAC activity. Therefore, we found that amitriptyline inhibited cyclin D2 transactivation and HDAC activity and could be a promising treatment for multiple myeloma.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China. xinliangmao@suda.edu.cn
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.forename: Wenjie
authors.initials: W
authors.lastname: Wang
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Fei
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D056741:Cyclin D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D056741:Cyclin D; D056572:Histone Deacetylase Inhibitors; D000639:Amitriptyline; D006655:Histone Deacetylases