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The tricyclic antidepressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases: in vitro and in silico evidence.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2011 Apr; Vol. 79 (4), pp. 672-80. Date of Electronic Publication: 2011 Jan 10. - Publication Year :
- 2011
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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.
- Subjects :
- Apoptosis physiology
Cell Cycle drug effects
Cell Cycle physiology
Cell Line, Tumor
Cell Survival drug effects
Cell Survival physiology
Cells, Cultured
Cyclin D metabolism
Histone Deacetylases metabolism
Humans
Multiple Myeloma enzymology
Multiple Myeloma pathology
Transcriptional Activation drug effects
Transcriptional Activation physiology
Amitriptyline pharmacology
Antidepressive Agents, Tricyclic pharmacology
Apoptosis drug effects
Cyclin D antagonists & inhibitors
Histone Deacetylase Inhibitors pharmacology
Multiple Myeloma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 79
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21220410
- Full Text :
- https://doi.org/10.1124/mol.110.068122