NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma
| Autor: | Yu-Tzu Tai, Laurence Catley, Remiszewski Stacy W, James D. Griffin, Richard Leblanc, Peter Atadja, Reshma Shringarpure, Robert L. Schlossman, Paul G. Richardson, Dharminder Chauhan, Kenneth C. Anderson, Ellen Weisberg, Nikhil C. Munshi, Nicholas Mitsiades, Teru Hideshima |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Proteasome Endopeptidase Complex
medicine.drug_class Poly ADP ribose polymerase Immunology Mice Nude Biology Hydroxamic Acids Biochemistry Dexamethasone Proto-Oncogene Proteins p21(ras) Immunocompromised Host Mice chemistry.chemical_compound Multienzyme Complexes Tumor Cells Cultured medicine Animals Humans Enzyme Inhibitors Glucocorticoids Interleukin-6 Cell growth Cell Cycle Histone deacetylase inhibitor NF-kappa B Acetylation Sodium butyrate Cell Biology Hematology Cell cycle Xenograft Model Antitumor Assays Molecular biology Up-Regulation Histone Deacetylase Inhibitors Cysteine Endopeptidases medicine.anatomical_structure Trichostatin A chemistry Cancer research Bone marrow Histone deacetylase Poly(ADP-ribose) Polymerases Multiple Myeloma medicine.drug |
| Zdroj: | Blood. 102:2615-2622 |
| ISSN: | 1528-0020 0006-4971 2615-2622 |
| DOI: | 10.1182/blood-2003-01-0233 |
| Popis: | 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. (Blood. 2003;102:2615-2622) |
| Databáze: | OpenAIRE |
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