Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells
Open Access
- 15 November 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 108 (10), 3441-3449
- https://doi.org/10.1182/blood-2006-04-016055
Abstract
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 α-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 α-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.This publication has 63 references indexed in Scilit:
- The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cellsBlood, 2005
- Proteasomal Degradation of Topoisomerase I Is Preceded by c-Jun NH2-Terminal Kinase Activation, Fas Up-Regulation, and Poly(ADP-Ribose) Polymerase Cleavage in SN38-Mediated Cytotoxicity against Multiple MyelomaCancer Research, 2004
- Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase InhibitorsClinical Cancer Research, 2004
- XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein ResponseMolecular and Cellular Biology, 2003
- NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myelomaBlood, 2003
- Molecular sequelae of histone deacetylase inhibition in human malignant B cellsBlood, 2003
- A Principal Role for the Proteasome in Endoplasmic Reticulum-associated Degradation of Misfolded Intracellular Cystic Fibrosis Transmembrane Conductance RegulatorOnline Journal of Public Health Informatics, 2002
- Ubiquitin-mediated proteolysis: biological regulation via destructionBioEssays, 2000
- Molecular chaperones in cellular protein foldingNature, 1996
- The ubiquitin-proteasome proteolytic pathwayCell, 1994