NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma

Abstract

Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM.

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.…”

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

“…Gastrointestinal toxicity and death have been reported in animal studies with higher doses of bortezomib and proteasome inhibition exceeding 90% than used in the present study. Several HDIs have been shown to have direct proteasome-inhibitory activity (55,56), providing a possible explanation for the increased toxicity of such a combination in normal as well as malignant epithelia. NF-nB -dependent or NF-nB -independent mechanisms involving proteasome or oxidative mechanisms could contribute to antitumor activity and systemic side effects (52 -58).…”

Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma

“…4B). Because we have shown that bortezomib (4) and other HDAC inhibitors (26,27) induce p21 Cip1 in MM.1S cells, we further examined expression of p21 Cip1 . Consistent to cell cycle profile, tubacin does not trigger induction of p21 Cip1 .…”