The Histone Deacetylase Inhibitor LBH589 Is a Potent Antimyeloma Agent that Overcomes Drug Resistance

Abstract

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acidderived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC 50 < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 upregulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients. (Cancer Res 2006; 66(11): 5781-9)

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

“…34 In vitro, JNJ-26481585 showed anti-proliferative activity against the 5T33MMvt cells at low nanomolar concentrations, which is in line with results described by Janine Arts et al 41 (submitted), demonstrating that JNJ-26481585 has high potency towards all class I HDAC enzymes (IC50 values of 0.11, 0.33 and 4.8 nM, for HDAC 1, 2 and 3, respectively). This suggests that hydroxamate-based HDAC inhibitors, JNJ-26481585 together with LBH589, 28 have higher anti-myeloma activity in vitro, working at nanomolar concentrations compared with others such as suberoylanilide hydroxamic acid 25 and NVP-LAQ824, 42 which are only effective at micromolar concentrations. By comparing the JNJ-26481585-induced histone acetylation and anti-proliferative effects in 5T33MMvt cells and STR-10 cells, we could conclude that the myeloma cells were more sensitive to the HDACi than BM endothelial cells.…”

“…This is in line with other studies, demonstrating that upregulation of p21 Waf1 is a hallmark for the HDACi-induced cell cycle arrest. 25,26,28,[43][44][45] This corresponds with the anti-proliferative activity of JNJ-26481585. However at 72 h incubation, cell cycle arrest is lost, most likely because of the large increase of apoptotic cells.…”

“…[21][22][23][24] Several broad-spectrum HDACi have already been shown to increase cell cycle inhibitors (p21, p27), inhibit the production of cytokines, such as IL-6 and VEGF, and induce apoptosis of MM cells in vitro. [25][26][27][28] Phase I clinical trials have also shown that some HDACi, such as suberoylanilide hydroxamic acid (SAHA), panobinostat and belinostat, are able to reduce tumor burden in patients with MM. [29][30][31] However, it is unclear, besides the direct in vitro effects on MM cells, how the BM microenvironment is affected by these HDACi, and more specifically how crucial processes like induction of bone disease and angiogenesis are affected.…”

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

“…Recent literature suggests that HDACs are also implicated in the drug resistance of B-cell malignancies such as multiple myeloma. 18,19 Given the causative role of HDACs in cancer, small molecular inhibitors of HDACs are expected to constitute a novel class of anticancer drugs. HDAC inhibitors are able to restore the expression of genes that are aberrantly repressed in tumor cells, leading to cell-cycle arrest, differentiation and apoptosis.…”

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

“…Bortezomib (Millennium Pharmaceuticals Inc., Cambridge, MA, USA), lenalidomide (Celgene Corporation, Summit, NJ, USA) and panobinostat (LBH589; Novartis Oncology, Varese, Italy) were dissolved in dimethyl sulfoxide (Sigma-Aldrich) and used at final doses of 7.5 nmol/l for 24 h (Roccaro et al, 2006), 1.75 mmol/l for 72 h (De Luisi et al, 2011) and 100 nmol/l for 72 h, respectively (Maiso et al, 2006). Cells were then lysed and tested by western blot as described above.…”