RRC ID 61877
Author Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D, Munshi NC, Schlossman R, Richardson P, Griffin J, Anderson KC.
Title NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma.
Journal Blood
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.
Volume 102(7)
Pages 2615-22
Published 2003-10-1
DOI 10.1182/blood-2003-01-0233
PII S0006-4971(20)44095-9
PMID 12816865
MeSH Acetylation / drug effects Animals Cell Cycle / drug effects Cysteine Endopeptidases / drug effects Cysteine Endopeptidases / metabolism Dexamethasone / pharmacology Enzyme Inhibitors / pharmacology* Glucocorticoids / pharmacology Histone Deacetylase Inhibitors* Humans Hydroxamic Acids / pharmacology* Immunocompromised Host Interleukin-6 / pharmacology Mice Mice, Nude Multienzyme Complexes / drug effects Multienzyme Complexes / metabolism Multiple Myeloma / drug therapy* NF-kappa B / metabolism Poly(ADP-ribose) Polymerases / metabolism Proteasome Endopeptidase Complex Proto-Oncogene Proteins p21(ras) / metabolism Tumor Cells, Cultured / drug effects Tumor Cells, Cultured / enzymology Up-Regulation / drug effects Xenograft Model Antitumor Assays
IF 17.794
Human and Animal Cells DT40(RCB1464) SHP2^(-) DT40(RCB1502)