NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma.
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.
Catley
Laurence
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Weisberg
Ellen
E
Tai
Yu-Tzu
YT
Atadja
Peter
P
Remiszewski
Stacy
S
Hideshima
Teru
T
Mitsiades
Nicholas
N
Shringarpure
Reshma
R
LeBlanc
Richard
R
Chauhan
Dharminder
D
Munshi
Nikhil C
NC
Schlossman
Robert
R
Richardson
Paul
P
Griffin
James
J
Anderson
Kenneth C
KC
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016867:Immunocompromised Host; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015850:Interleukin-6; C477361:LAQ824; D009097:Multienzyme Complexes; D016328:NF-kappa B; D003907:Dexamethasone; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)