Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell

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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Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2011.38.3265 ◽

2012 ◽

Vol 30 (18) ◽

pp. 2204-2210 ◽

Cited By ~ 110

Author(s):

Guillermo Garcia-Manero ◽

Francesco Paolo Tambaro ◽

Nebiyou B. Bekele ◽

Hui Yang ◽

Farhad Ravandi ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Acute Myelogenous Leukemia ◽

Single Agent ◽

Complete Response ◽

Myelogenous Leukemia ◽

Platelet Recovery ◽

Free Survival ◽

Binding Factor ◽

Deacetylase Inhibitor ◽

Acute Myelogenous

Purpose To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and Methods Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. Results After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. Conclusion The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

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Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-2260 ◽

2016 ◽

Vol 22 (14) ◽

pp. 3560-3570 ◽

Cited By ~ 23

Author(s):

Andrea Muscat ◽

Dean Popovski ◽

W. Samantha N. Jayasekara ◽

Fernando J. Rossello ◽

Melissa Ferguson ◽

...

Keyword(s):

Tumor Growth ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitor ◽

Low Dose ◽

Growth Arrest ◽

Lineage Differentiation ◽

Deacetylase Inhibitor ◽

Rhabdoid Tumors ◽

Inhibitor Treatment

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Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

Cells ◽

10.3390/cells9071677 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1677

Author(s):

Håkon Reikvam

Keyword(s):

Acute Myelogenous Leukemia ◽

Metabolic Regulation ◽

Leukemia Cell ◽

Gene Mutations ◽

Nuclear Factor Κb ◽

Myelogenous Leukemia ◽

Nucleic Acid Binding ◽

Gene Expressions ◽

Expression Of Genes ◽

Acute Myelogenous

Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

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26 HISTONE DEACETYLASE INHIBITOR SCRIPTAID IMPROVES EPIGENETIC REPROGRAMMING AND CLONING EFFICIENCY IN THE PIG

Reproduction Fertility and Development ◽

10.1071/rdv27n1ab26 ◽

2015 ◽

Vol 27 (1) ◽

pp. 105

Author(s):

S. Liang ◽

T. Kim ◽

N.-H. Kim ◽

X.-S. Cui

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitor ◽

Histone H3 ◽

Development Program ◽

Donor Cell ◽

Epigenetic Reprogramming ◽

Republic Of Korea ◽

Cloning Efficiency ◽

Cell Stage ◽

Deacetylase Inhibitor

After somatic cell nuclear transfer (SCNT), the epigenetic state of a differentiated donor cell nucleus must be reversed to the embryonic state. Incomplete epigenetic reprogramming and abnormal gene activation of the donor cell nuclei is thought to be the cause of low cloning efficiency. To improve cloning efficiency, we investigated the effect of scriptaid, a novel histone deacetylase inhibitor, on the in vitro development of porcine SCNT embryos were investigated. Cumulus cells collected from cumulus-oocyte complexes (COC) after 44 h of maturation were used for donor cell, and embryos were cultured in porcine zygote medium (PZM)-5 medium for 7 days. We found that treating SCNT embryos with 300 or 500 nM scriptaid for 20 h after activation increased developmental rate to the blastocyst stage (300 nM, 26.2%; 500 nM, 24.6% v. 100 nM, 18.3%; Ctrl, 15.7%; P < 0.05) and total cell numbers (300 nM, 43.5; 500 nM, 40.8 v. 100 nM, 33.8; Ctrl, 32.3; P < 0.05). Additionally, results of the TUNEL assay indicated that scriptaid decreased apoptosis (300 nM, 6.8% v. Ctrl, 11.4%; P < 0.05) in SCNT blastocysts. After the 300 nM scriptaid treatment, the levels of acetylated histone H3 lysine 9 and 5-hydroxymethylcytosines were increased (P < 0.05), and histone H3 lysine 9 trimethylation and 5-methylcytosine were decreased at the 1-cell stage, which might explain the enhanced (P < 0.05) transcript levels of mir-152, Oct4, Cdx2, and Bcl-xL and reduced (P < 0.05) transcription of Dnmt1, Casp3, and Bax in blastocysts. In conclusion, scriptaid enhances the developmental capacity by preventing apoptosis, and improves nuclear reprogramming in porcine SCNT embryos.This work was supported by the Bio-industry Technology Development Program, Ministry of Agriculture, Food and Rural Affairs, Republic of Korea, and by a grant from the Next-Generation BioGreen 21 Program (No. PJ009601 and PJ009098), Rural Development Administration, Republic of Korea.

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