Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells.
Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells. LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional therapies via caspase activation and poly-(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of bortezomib in combination with LBH589.
Catley
Laurence
L
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Weisberg
Ellen
E
Kiziltepe
Tanyel
T
Tai
Yu-Tzu
YT
Hideshima
Teru
T
Neri
Paola
P
Tassone
Pierfrancesco
P
Atadja
Peter
P
Chauhan
Dharminder
D
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D000077767:Panobinostat; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011480:Protease Inhibitors; D011719:Pyrazines; D014404:Tubulin; D050257:Tubulin Modulators; D000069286:Bortezomib; D000077767:Panobinostat; D006867:Hydrolases