Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway.
Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. The optimal combination was validated in MV4-11 xenografts. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted.
Zhou
J
J
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Pan
M
M
Xie
Z
Z
Loh
S-L
SL
Bi
C
C
Tai
Y-C
YC
Lilly
M
M
Lim
Y-P
YP
Han
J-H
JH
Glaser
K B
KB
Albert
D H
DH
Davidsen
S K
SK
Chen
C-S
CS
D000208:Acute Disease; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003561:Cytarabine / Q000008:administration & dosage; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D017231:Proto-Oncogene Proteins c-mos / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
D018797:Cell Cycle Proteins; D007191:Indazoles; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D003561:Cytarabine; D004317:Doxorubicin; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases; D017231:Proto-Oncogene Proteins c-mos; D020928:Mitogen-Activated Protein Kinases