Abstract:
:Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Therefore, HDAC inhibitors used alone and in combination are being actively studied as novel therapies in MM. In the present study, we investigated the preclinical activity of ACY-1215, an HDAC6-selective inhibitor, alone and in combination with bortezomib in MM. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted endoplasmic reticulum stress and apoptosis via activation of caspase-3, caspase-8, and caspase-9 and poly (ADP) ribosome polymerase. In vivo, the anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using 2 different xenograft SCID mouse models: human MM injected subcutaneously (the plasmacytoma model) and luciferase-expressing human MM injected intravenously (the disseminated MM model). Tumor growth was significantly delayed and overall survival was significantly prolonged in animals treated with the combination therapy. Pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 hours after treatment coincident with an increase in acetylated α-tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blot analysis. These studies provide preclinical rationale for acetylated α-tubulin use as a pharmacodynamic biomarker in future clinical trials.
journal_name
Bloodjournal_title
Bloodauthors
Santo L,Hideshima T,Kung AL,Tseng JC,Tamang D,Yang M,Jarpe M,van Duzer JH,Mazitschek R,Ogier WC,Cirstea D,Rodig S,Eda H,Scullen T,Canavese M,Bradner J,Anderson KC,Jones SS,Raje Ndoi
10.1182/blood-2011-10-387365subject
Has Abstractpub_date
2012-03-15 00:00:00pages
2579-89issue
11eissn
0006-4971issn
1528-0020pii
blood-2011-10-387365journal_volume
119pub_type
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