Submitted April 14, 2006
Accepted May 1, 2006
Aggresome induction by proteasome inhibitor bortezomib
and 
-tubulin hyperacetylation by tubulin
deacetylase (TDAC) inhibitor LBH589 are synergistic in
myeloma cells
Laurence Catley, Ellen Weisberg, Tanyel Kiziltepe, Yu-Tzu Tai, Teru Hideshima, Paola Neri, Pierfrancesco Tassone, Peter Atadja, Dharminder Chauhan, Nikhil C Munshi, and Kenneth C Anderson*
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Novartis Institutes for Biomedical Research, Oncology Research
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
Histone deacetylase (HDAC) inhibitors have shown
cytotoxicity as single agents in pre-clinical 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 which were
sensitive and resistant to Dexamethasone (Dex), as well
as primary patient MM cells. LBH589 at low nanomolar
concentrations also induced 
-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 -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.
