Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
Oncology Division, University of Navarra, Pamplona, Spain.
A
A
Vilas-Zornoza
X
X
Agirre
G
G
Abizanda
C
C
Moreno
V
V
Segura
A
A
De Martino Rodriguez
E S
ES
José-Eneriz
E
E
Miranda
J I
JI
Martín-Subero
L
L
Garate
M J
MJ
Blanco-Prieto
J A
JA
García de Jalón
P
P
Rio
J
J
Rifón
J C
JC
Cigudosa
J A
JA
Martinez-Climent
J
J
Román-Gómez
M J
MJ
Calasanz
J M
JM
Ribera
F
F
Prósper
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007211:Indoles; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D000077767:Panobinostat; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D014750:Vincristine; D003907:Dexamethasone; D000077767:Panobinostat