Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells

Abstract

<jats:title>Abstract</jats:title><jats:p>DNMT inhibitors are promising new drugs for cancer therapies. In this study, we have observed the antileukemic action of two diverse DNMT inhibitors, the nucleoside agent zebularine and the non-nucleoside agent RG108, in human promyelocytic leukemia (PML) HL-60 cells. Zebularine but not RG108 caused dose- and time-dependent cell growth inhibition and induction of apoptosis. However, co-treatment with either drug at a non-toxic dose and all trans retinoic acid (RA) reinforced differentiation to granulocytes, while 24 or 48 h-pretreatment with zebularine or RG108 followed by RA alone or in the presence of HDAC inhibitors (sodium phenyl butyrate or BML-210) significantly accelerated and enhanced cell maturation to granulocytes. This occurs in parallel with the expression of a surface biomarker, CD11b, and early changes in histone H4 acetylation and histone H3K4me3 methylation. The application of both drugs to HL-60 cells in continuous or sequential fashion decreased DNMT1 expression, and induced E-cadherin promoter demethylation and reactivation at both the mRNA and the protein levels in association with the induction of granulocytic differentiation. The results confirmed the utility of zebularine and RG108 in combinations with RA and HDAC inhibitors to reinforce differentiation effects in promyelocytic leukemia.</jats:p>

DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5

“…RG108 ameliorated the SBMA model cell viability in a dose-dependent manner ( Fig 2G). Although DNMTs' levels were not affected by low doses of RG108, higher concentrations (1 and 10 lM) of RG108 reduced the expression of Dnmt1 but not that of Dnmt3a or Dnmt3b, similar to that reported previously in cancer cells (Savickiene et al, 2012;Gracia et al, 2014), suggesting that RG108 is relatively specific to Dnmt1 in the NSC97Q cells ( Fig 2H). RG108 did not change the cell viability of DHT-untreated NSC97Q cells or DHT-treated NSC24Q cells as evaluated with WST-8 assay (Fig 2I and J).…”

The promoter of miR-663 is hypermethylated in Chinese pediatric acute myeloid leukemia (AML)

“…These include aberrations in methylation, which is a key epigenetic event responsible for enhanced proliferation and self-renewal, differentiation arrest, and impaired apoptosis of leukemic cells [4]. Inactivation of tumor suppressor genes by promoter hypermethylation has been increasingly recognized as a key event for leukemia, with silencing of tumor suppressor genes by aberrant DNA hypermethylation reported in hematologic malignancies, including subsets of AML [5-8]. Compared to the incidences of DNA mutations and deletions, the frequency of aberrant DNA methylation of tumor suppressor genes is high in AML.…”

Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98–HOXA9-induced myeloid disease

“…VPA also did not reduce runx1/c-myb expression in tNHA9 embryos compared to DMSO controls (41/68 vs. 57/72 high expression, respectively) (Figure 5B,H). These findings suggest that HDAC inhibitors may not be as effective as DNMT inhibitors at blocking the full impact of NHA9 activity, especially within the HSC compartment.Recent studies propose that combining HDAC and DNMT inhibitors may work better than either compound alone to restore normal epigenetic regulation in patients with myeloid disease 47,48. Thus, we sought to see if targeting both of these epigenetic mechanisms simultaneously would yield a therapeutic response.20Indeed, when we combined as little as 10 μM DAC and 25 μM VPA (13% and 10% of each monotherapy dose), we restored wild-type levels of lcp1 (39/60) at 30 hpf, and of runx1/c-myb (46/58) at 36 hpf(Figure 5C,D,G,H), in tNHA9 embryos.…”