Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists.
Stromal cell derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are involved in the directional homing to the bone marrow niches and in peripheral mobilization of normal and transformed hematopoietic stem and myeloid progenitor cells. Elevated CXCR4 expression confers poor prognosis, whereas inhibition of CXCR4 signaling overcomes stroma-mediated chemoresistance in acute myeloid leukemia (AML). Here, we demonstrate that treatment with the pan-histone deacetylase inhibitor panobinostat (PS) depleted the mRNA and protein levels of CXCR4 in the cultured and primary AML cells. PS-induced acetylation of the heat shock protein (hsp) 90 reduced the chaperone association between CXCR4 and hsp90, directing CXCR4 to degradation by the 20S proteasome. PS treatment also depleted G protein-coupled receptor kinase 3, as well as attenuated the phosphorylation of AKT and ERK1/2 in AML cells, which was not affected by cotreatment with CXCL12. Compared with each agent alone, cotreatment with PS and CXCR4 antagonist AMD3100 or FC-131 synergistically induced apoptosis of cultured and primary AML cells. PS and FC-131 exerted more lethal effects on primary AML versus normal CD34(+) bone marrow progenitor cells. These findings support the rationale to test the in vivo efficacy of PS in enhancing the lethal effects of CXCR4 antagonists against AML cells.
Mandawat
Aditya
A
Medical College of Georgia Cancer Center, Augusta, GA, USA.
Fiskus
Warren
W
Buckley
Kathleen M
KM
Robbins
Kelly
K
Rao
Rekha
R
Balusu
Ramesh
R
Navenot
Jean-Marc
JM
Wang
Zi-Xuan
ZX
Ustun
Celalettin
C
Chong
Daniel G
DG
Atadja
Peter
P
Fujii
Nobutaka
N
Peiper
Stephen C
SC
Bhalla
Kapil
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D000080027:Cyclams; D004357:Drug Synergism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D000077767:Panobinostat; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C496951:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl); D000077767:Panobinostat; C088327:plerixafor