Epigenetic therapy of acute myeloid leukemia using 5-aza-2'-deoxycytidine (decitabine) in combination with inhibitors of histone methylation and deacetylation

Abstract

BackgroundThe silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation occurs frequently in acute myeloid leukemia (AML). This epigenetic alteration can be reversed by 5-aza-2’-deoxcytidine (decitabine, 5-AZA-CdR). Although 5-AZA-CdR can induce complete remissions in patients with AML, most patients relapse. The effectiveness of this therapy may be limited by the inability of 5-AZA-CdR to reactivate all TSGs due to their silencing by other epigenetic mechanisms such as histone methylation or chromatin compaction. EZH2, a subunit of the polycomb repressive complex 2, catalyzes the methylation of histone H3 lysine 27 (H3K27) to H3K27me3. 3-Deazaneplanocin-A (DZNep), an inhibitor of methionine metabolism, can reactivate genes silenced by H3K27me3 by its inhibition of EZH2. In a previous report, we observed that 5-AZA-CdR, in combination with DZNep, shows synergistic antineoplastic action against AML cells. Gene silencing due to chromatin compaction is attributable to the action of histone deacetylases (HDAC). This mechanism of epigenetic gene silencing can be reversed by HDAC inhibitors such as trichostatin-A (TSA). Silent TSGs that cannot be reactivated by 5-AZA-CdR or DZNep have the potential to be reactivated by TSA. This provides a rationale for the use of HDAC inhibitors in combination with 5-AZA-CdR and DZNep to treat AML.ResultsThe triple combination of 5-AZA-CdR, DZNep, and TSA induced a remarkable synergistic antineoplastic effect against human AML cells as demonstrated by an in vitro colony assay. This triple combination also showed a potent synergistic activation of several key TSGs as determined by real-time PCR. The triple combination was more effective than the combination of two agents or a single agent. Microarray analysis showed that the triple combination generated remarkable changes in global gene expression.ConclusionsOur data suggest that it may be possible to design a very effective therapy for AML using agents that target the reversal of the following three epigenetic “lock” mechanisms that silence gene expression: DNA methylation, histone methylation, and histone deacetylation. This approach merits serious consideration for clinical investigation in patients with advanced AML.

Synergistic antineoplastic action of 5-aza-2'deoxycytidine (decitabine) in combination with different inhibitors of enhancer of zeste homolog 2 (EZH2) on human lung carcinoma cells

“…Caspases play an important role in the regulation and execution of apoptotic cell death [34]. We reported previously that 5-Aza-CdR in combination with DZNep induces a synergistic induction of apoptosis in leukemia cells [35]. We observed that the combination of these epigenetic agents also induce apoptosis in lung carcinoma cells.…”

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

“…EZH2 and FOXP3 are both involved in the inhibition of autoimmunity and antitumor immunity by Treg cells [129,130], whereas EZH2 itself is involved in the resistance of tumor cells to chemotherapy [111,113] and radiotherapy [131]. Preclinical studies indicate that EZH2 inhibitors are applicable for cancer chemotherapy in combination with other anticancer drugs, such as topoisomerase II inhibitor [111], EGFR inhibitor [132], VEGFR2 inhibitor [133] or HDAC inhibitor [134]. Recently, immune-checkpoint blockers, including anti-CTLA4 antibody, anti-PD1 (PDCD1) antibody and anti-PDL1 (CD274) antibody, are emerging as a new class of cancer therapeutics that augment antitumor immunity [130].…”

Combination of resveratrol and 5‐azacytydine improves osteogenesis of metabolic syndrome mesenchymal stem cells

“…ASC senescence and ageing, which is associated with DNA methylation, can be diminished by the application of DNA methyltransferase (DNMT) inhibitors, such as 5‐azacitidine (5‐AZA), which inhibits the methylation pattern of specific gene regions, while activating associated genes. 5‐AZA is chemically an analogue of cytidine, commonly used in the treatment of acute myelogenous leukaemia 24. However, it was shown in human‐aged ASCs that 5‐AZA reversed their aged phenotype, increased proliferative activity and improved osteogenic differentiation potential, while it decreased the accumulation of OS factors and DNA methylation status 25.…”