scholarly journals Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

Leukemia ◽  
2008 ◽  
Vol 22 (12) ◽  
pp. 2159-2168 ◽  
Author(s):  
C Nishioka ◽  
T Ikezoe ◽  
J Yang ◽  
H P Koeffler ◽  
A Yokoyama
Keyword(s):  
Histone Deacetylase ◽  
Acute Myelogenous Leukemia ◽  
Histone Deacetylase Inhibitor ◽  
Growth Arrest ◽  
Mtor Signaling ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Deacetylase Inhibitor ◽  
Acute Myelogenous ◽  
Induce Growth Arrest

scholarly journals Blockade of mTOR Signaling Potentiates the Ability of Histone Deacetylase Inhibitor to Induce Growth Arrest and Differentiation of Acute Myelogenous Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1612-1612
Author(s):  
Chie Nishioka ◽  
Takayuki Ikezoe ◽  
Yang Jing ◽  
H. Phillip Koeffler ◽  
Akihito Yokoyama
Keyword(s):  
Histone Deacetylase ◽  
Acute Myelogenous Leukemia ◽  
Histone Deacetylase Inhibitor ◽  
Mtor Signaling ◽  
Myelogenous Leukemia ◽  
Human Leukemia ◽  
Cell Surface Antigens ◽  
Nb4 Cells ◽  
Deacetylase Inhibitor ◽  
Acute Myelogenous

Abstract This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mTOR signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K), and p-S6K by Western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analogue RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27 kip1 and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce expression of the myeloid differentiation-related transcription factor CCAAT enhancer binding protein e in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of a HDACI and a mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.

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