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.
Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent.
Deleu
S
S
Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), B-1090 Brussels, Belgium.
Lemaire
M
M
Arts
J
J
Menu
E
E
Van Valckenborgh
E
E
King
P
P
Vande Broek
I
I
De Raeve
H
H
Van Camp
B
B
Croucher
P
P
Vanderkerken
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001847:Bone Diseases / Q000188:drug therapy / Q000209:etiology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010014:Osteolysis / Q000188:drug therapy / Q000209:etiology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C541788:quisinostat