title: Histone deacetylase inhibitors demonstrate significant preclinical activity as single agents, and in combination with bortezomib in Waldenström's macroglobulinemia.
abstract: We studied the role of histone deacetylase inhibitors in Waldenstrom's macroglobulinemia (WM). Gene expression profiling of bone marrow CD19+ cells from 30 patients and 10 healthy donors showed overexpression of HDAC4, HDAC9, and Sirt5, with validation of HDAC9 overexpression by q-PCR in primary and BCWM.1 cells. Suberoylanilide hydroxamic acid, trichostatin A, panobinostat, and sirtinol demonstrated dose-dependent killing of BCWM.1 cells. TSA showed the greatest potency with IC50 of 70 nM. Importantly, HDAC9 activity was decreased following TSA treatment suggesting an essential role for this HDAC in WM therapy. The combination of bortezomib plus HDAC inhibitors resulted in at least additive tumor cell killing in BCWM.1 cells. TSA and bortezomib-induced apoptosis depended on a similar set of caspase activation, whereas their effect on cell cycle regulators was distinctly different. These results provided a framework for examining HDAC inhibitors as monotherapy, as well as combination therapy with bortezomib in WM.
authors: Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors: Jenny Y
authors: JY
authors: Sun
authors: Lian
authors: L
authors: Xu
authors: Hsuyi
authors: H
authors: Tseng
authors: Bryan
authors: B
authors: Ciccarelli
authors: Mariateresa
authors: M
authors: Fulciniti
authors: Zachary R
authors: ZR
authors: Hunter
authors: Kaveh
authors: K
authors: Maghsoudi
authors: Evdoxia
authors: E
authors: Hatjiharissi
authors: Yangsheng
authors: Y
authors: Zhou
authors: Guang
authors: G
authors: Yang
authors: Biao
authors: B
authors: Zhu
authors: Xia
authors: X
authors: Liu
authors: P
authors: P
authors: Gong
authors: Leukothea
authors: L
authors: Ioakimidis
authors: Patricia
authors: P
authors: Sheehy
authors: Christopher J
authors: CJ
authors: Patterson
authors: Nikhil C
authors: NC
authors: Munshi
authors: Owen A
authors: OA
authors: O'Connor
authors: Steven P
authors: SP
authors: Treon
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000201:enzymology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D015151:Immunoblotting; D008297:Male; D016133:Polymerase Chain Reaction; D011719:Pyrazines / Q000008:administration & dosage; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; C012589:trichostatin A; D000069286:Bortezomib; D006655:Histone Deacetylases