Abstract
Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes.
Highlights
Besides the widely accredited genetic variation, a disrupted epigenetic outline is a well-documented hallmark of the cancer phenotype [1,2,3,4,5]
suberoylanilide hydroxamic acid (SAHA) and DAC showed a significant reduction in the proliferation of both acute myeloid leukemia (AML) cell lines in a dose- and time-dependent fashion (Figure 1)
A more pronounced effect was obtained by SAHA treatment on the U937 cell line, where 88.5% reduction in cell viability was attained after 48 h of treatment with an IC50 of 2.2 μM (Figure 1B)
Summary
Besides the widely accredited genetic variation, a disrupted epigenetic outline is a well-documented hallmark of the cancer phenotype [1,2,3,4,5]. Atypical mechanisms of DNA methylation and histone acetylation, which covalently modulate chromatin architecture, play a critical role in inducing aberrant transcription of key genes regulating basic cellular processes such as cell proliferation, cell cycle regulation, and apoptosis, giving rise to a cellular growth advantage in tumor cells [1,6]. A non-permissive condensed chromatin configuration is promoted by removal of acetyl groups from lysine residues in histones, histone deacetylation, as governed by histone deacetylases (HDACs). This configuration is associated with transcriptional gene silencing. Increased activity of HDACs, their irregular recruitment to target gene-promoters, along with reduced activity of their counter parts, histone acetyl transferases (HATs) impair normally balanced acetylation in favor of hypoacetylation and intensify the tumorigenic process [6,9].
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