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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Mao X,Hou T,Cao B,Wang W,Li Z,Chen S,Fei M,Hurren R,Gronda M,Wu D,Trudel S,Schimmer ADdoi
10.1124/mol.110.068122subject
Has Abstractpub_date
2011-04-01 00:00:00pages
672-80issue
4eissn
0026-895Xissn
1521-0111pii
mol.110.068122journal_volume
79pub_type
杂志文章abstract::To study the functional role of individual alpha1-adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the alpha1B-AR and/or alpha1D-AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the alpha1D-AR knockout and alpha1B-/alpha1D-AR...
journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
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pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:1994-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-04-01 00:00:00
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pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:1998-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:2014-02-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000169
更新日期:2021-02-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:2003-10-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::The 5'-flanking region of the mouse mu opioid receptor (MOR) gene has two promoters, referred to as distal and proximal. MOR mRNA is predominantly initiated by the proximal promoter. Previously, several important cis-elements and trans-factors have been shown to play a functional role in the proximal promoter of the M...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008284
更新日期:2005-05-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:2005-04-01 00:00:00