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Effect of pan-histone deacetylase inhibitor panobinostat (LBH589) on CXCR4 levels and signaling and on anti-leukemia activity in combination with CXCR4 antagonists

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

NlmCategory="UNASSIGNED">14541 Background: Bone marrow stroma-derived factor-1 (SDF-1, CXCL12) binds and activates the chemokine receptor CXCR4, which regulates the trafficking and mobilization of normal and leukemic hematopoietic cells. CXCR4 signaling thorough AKT and c-Raf also promotes survival and decreases sensitivity of AML cells to anti-leukemia agents. Both CXCL12 and CXCR4 are overexpressed and confer poor prognosis in AML. Treatment with the CXCR4 antagonist AMD3100 sensitizes AML cells to anti-leukemia drugs. We determined the effect of panobinostat (P) and/or FC-131 (a new generation CXCR4 inverse agonist) on CXCR4 expression and signaling in cultured and primary AML cells. Following treatment of human AML OCI-AML3, HL-60, and Jurkat cells, as well as primary AML cells with P (10 to 50 nM) and/or FC-131 (10 nM) with our without 10 nM of CXCL12, cell surface expression of CXCR4 and apoptosis (Annexin V/PI staining) were determined by flow cytometry. Intracellular protein levels of CXCR4, p-AKT, p-ERK1/2, heat shock protein (hsp) 70 and hsp90 were determined by immunoblot (IB) analyses. Binding of CXCR4 to hsp90 and hsp70, as well as CXCR4 acetylation, were determined by immunoprecipitation (IP)/IB analyses. Treatment with P depleted the intracellular and surface expression of CXCR4 in the presence or absence of CXCL12. P induced acetylation of hsp90 and decreased its binding to CXCR4. P also induced acetylation and increased membrane binding of CXCR4 to hsp70. P promoted degradation of CXCR4 by the proteasome. Treatment with P alone also decreased p-AKT and p-ERK1/2. Co- treatment with P markedly attenuated the phosphorylation (p) of AKT and ERK1/2 induced by CXCL12, casuing apoptosis of up to 50% of cultured and primary AML cells. Co-treatment with P and FC-131 caused greater depletion of CXCR4, p-AKT and p-ERK1/2 levels, and synergistically induced apoptosis of the cultured AML cells (combination indices of < 1.0, utilizing isobologram analysis). CXCR4 is chaperoned by hsp90, and treatment with P depletes CXCR4 levels and signaling in AML cells. The novel combination of FC-131 and P is synergistically active and its in vivo ant-AML efficacy is currently under evaluation. [Table: see text].

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Accession: 057707770

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PMID: 27950012

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