RT Journal Article SR Electronic T1 The Tricyclic Antidepressant Amitriptyline Inhibits d-Cyclin Transactivation and Induces Myeloma Cell Apoptosis by Inhibiting Histone Deacetylases: In Vitro and In Silico Evidence JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 672 OP 680 DO 10.1124/mol.110.068122 VO 79 IS 4 A1 Mao, Xinliang A1 Hou, Tingjun A1 Cao, Biyin A1 Wang, Wenjie A1 Li, Zhihua A1 Chen, Suning A1 Fei, Min A1 Hurren, Rose A1 Gronda, Marcela A1 Wu, Depei A1 Trudel, Suzanne A1 Schimmer, Aaron D. YR 2011 UL http://molpharm.aspetjournals.org/content/79/4/672.abstract AB 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 G0/G1 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.