Combination treatment of p53-null HL-60 cells with Histone Deacetylase Inhibitors and Chlorambucil Augments Apoptosis and Increases BCL6 and p21 Gene Expression

Kwa, F, Cole-Sinclair, M and Kapuscinski, K 2019, 'Combination treatment of p53-null HL-60 cells with Histone Deacetylase Inhibitors and Chlorambucil Augments Apoptosis and Increases BCL6 and p21 Gene Expression', Current Molecular Pharmacology, vol. 12, no. 1, pp. 72-81.


Document type: Journal Article
Collection: Journal Articles

Title Combination treatment of p53-null HL-60 cells with Histone Deacetylase Inhibitors and Chlorambucil Augments Apoptosis and Increases BCL6 and p21 Gene Expression
Author(s) Kwa, F
Cole-Sinclair, M
Kapuscinski, K
Year 2019
Journal name Current Molecular Pharmacology
Volume number 12
Issue number 1
Start page 72
End page 81
Total pages 10
Publisher Bentham Science Publishers Ltd.
Abstract Background: Treatment of hematological malignancies with conventional DNA-damaging drugs, such as chlorambucil (CLB), commonly results in p53-dependent chemo-resistance. Chromatin modifying agents, such as histone deacetylase inhibitors (HDACIs), sodium butyrate (NaBu) and trichostatin A (TSA), may reverse chemo-resistance by modulating the activity of chromatin remodeling enzymes and/or genes that control cell proliferation, differentiation and survival. Objective: This study examined the potential use of HDACIs and CLB combination therapies in an in vitro chemo-resistant leukemia model. Methods: The p53-null promyelocytic leukemia cell line, HL60, was used as an in vitro model of chemo-resistant leukemia. Drug cytotoxicity was determined by tetrazolium salt-based colorimetric assays and Annexin V/propidium iodide staining (flow cytometry). The level of mRNA expression of the chromatin modifying genes was measured by quantitative real-time PCR. Results: Micromolar concentrations of CLB combined with either NaBu or TSA triggered synergistic cytotoxic effects in HL-60 cells (p < 0.001). The effects of the combination treatments resulted in upregulated p21 gene expression (up to 59-fold; p<0.001) that preceded an increase in BCL6 gene expression (up to 20-fold; p < 0.001). Statistically significant but smaller magnitude changes (≤ 2-fold; p <0.05) were noted in the expression of other genes studied regardless of the treatment type. Conclusion: The combination treatment of p53-null HL-60 cells with DNA-damaging agent CLB and HDACIs NaBu and TSA triggered additive to synergistic effects on apoptosis and upregulated BCL6 and p21 expression. These findings reveal BCL6 and p21 as potential targets of chemo-resistance for the development of anti-leukemic drugs.
Subject Molecular Medicine
Keyword(s) Chlorambucil
chromatin
drug resistance
cyclin-dependent kinase inhibitor p21
histone deacetylase inhibitors
proto-oncogene BCL6
sodium butyrate
trichostatin A
DOI - identifier 10.2174/1874467211666181010161836
Copyright notice © 2019 Bentham Science Publishers
ISSN 1874-4672
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