Combined Treatment with Low Concentrations of Decitabine and SAHA Causes Cell Death in Leukemic Cell Lines but Not in Normal Peripheral Blood Lymphocytes

Abstract

Epigenetic therapy reverting aberrant acetylation or methylation offers the possibility to target preferentially tumor cells and to preserve normal cells. Combination epigenetic therapy may further improve the effect of individual drugs. We investigated combined action of demethylating agent decitabine and histone deacetylase inhibitor SAHA (Vorinostat) on different leukemic cell lines in comparison with peripheral blood lymphocytes. Large decrease of viability, as well as huge p21WAF1 induction, reactive oxygen species formation, and apoptotic features due to combined decitabine and SAHA action were detected in leukemic cell lines irrespective of their p53 status, while essentially no effect was observed in response to the combined drug action in normal peripheral blood lymphocytes of healthy donors. p53-dependent apoptotic pathway was demonstrated to participate in the wtp53 CML-T1 leukemic cell line response, while significant influence of reactive oxygen species on viability decrease has been detected in p53-null HL-60 cell line.

Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

“…This result explains, at least in part, the greater degree of apoptosis induction in the U937 cell line by the epigenetic combination therapy that is stimulating both the intrinsic and the extrinsic apoptotic pathways. In accordance with our results, a previous study showed that the treatment of AML cell lines, CML-T1 and HL-60, with a combination of SAHA and DAC upregulated the cleavage of procaspase 3 and 7 and induced the p53-dependent apoptotic way of cell death in CML-T1 [46].…”

“…We observed a significant time-and dose-dependent inhibition of cell growth using either epigenetic modulator. Previous reports have documented that inhibitors of HDACs and DNMTs have selective, anti-proliferative effects on multiple cancer cell lines, including AML cell lines, while maintaining normal viability and proliferation of normal blood cells [25,45,46]. The HDAC inhibitors-valproic acid, trichostatin A, and sodium butyrate-inhibited leukemic cell proliferation in a dose-dependent manner [45].…”

Decitabine and SAHA-Induced Apoptosis Is Accompanied by Survivin Downregulation and Potentiated by ATRA in p53-Deficient Cells

“…Expression of proapototic BAX protein only moderately increased in response to DAC + SAHA + ATRA treatment of HL-60 cells, but its mitochondrial localization in apoptotic cells indicating mitochondrial apoptotic pathway was found like it was documented in DAC + SAHA treated cells [5]. Negative correlation between survivin and BAX expression was detected in DAC + SAHA + ATRA-treated cells by flow-cytometry confirming again the relationship between loss of survivin expression and apoptosis (Figure 5).…”

Synergy between HDAC and PARP Inhibitors on Proliferation of a Human Anaplastic Thyroid Cancer-Derived Cell Line

“…Current cancer therapy should satisfy requirements for targeted elimination of cancer cells simultaneously with life-compatible adverse effects [ 10 ]. One of the main tenets of cancer therapeutics is that combinations of anticancer agents with different targets or different mechanisms of action and varied normal tissue toxicities will produce better therapeutic outcomes [ 11 ] by decreasing single drugs doses and minimizing or slowing drug resistance development.…”