+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists



Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists



Blood 116(24): 5306-5315



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 054853025

Download citation: RISBibTeXText

PMID: 20810927

DOI: 10.1182/blood-2010-05-284414


Related references

Effect of pan-histone deacetylase inhibitor panobinostat (LBH589) on CXCR4 levels and signaling and on anti-leukemia activity in combination with CXCR4 antagonists. Journal of Clinical Oncology 26(15_suppl): 14541-14541, 2016

Pan-histone deacetylase (HDAC) inhibitor LBH589 depletes CXCR4 levels combination with CXCR4 antagonists.. 2007

Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration. Cancer Biology & Therapy 14(2): 175-183, 2013

Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 114(24): 5024-5033, 2010

Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor. Leukemia Research 35(9): 1212-1218, 2011

Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. Journal of Endocrinological Investigation, 2017

The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy 6(7): 976-978, 2011

Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors. Molecular Cancer Therapeutics 11(11): 2373-2383, 2013

The dual EGFR/HER2 inhibitor lapatinib synergistically enhances the antitumor activity of the histone deacetylase inhibitor panobinostat in colorectal cancer models. Cancer Research 71(10): 3635-3648, 2011

The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Clinical Cancer Research 16(15): 3923-3932, 2010

Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114(13): 2733-2743, 2009

The Histone Deacetylase Inhibitor Valproic Acid Exerts a Synergistic Cytotoxicity with the DNA-Damaging Drug Ellipticine in Neuroblastoma Cells. International Journal of Molecular Sciences 19(1), 2018

Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Molecular Cancer Therapeutics 11(4): 973-983, 2012

The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis, down-regulates the CXCR4 chemokine receptor and impairs migration of chronic lymphocytic leukemia cells. Haematologica 95(7): 1136-1143, 2010

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo. International Journal of Cancer 130(3): 694-704, 2012