HDAC and HMT Inhibitors in Combination with Conventional Therapy: A Novel Treatment Option for Acute Promyelocytic Leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by PML-RARA translocation, which causes the blockage of promyelocyte differentiation. Conventional treatment with Retinoic acid and chemotherapeutics is quite satisfactory. However, there are still patients who relapse or develop resistance to conventional treatment. To propose new possibilities for acute leukemia treatment, we studied the potential of histone deacetylase (HDAC) inhibitor and histone methyl transferase (HMT) inhibitor to enhance conventional therapy in vitro and ex vivo. NB4 and HL60 cell lines were used as an in vitro model; APL patient bone marrow mononuclear cells were used as an ex vivo model. Cell samples were treated with Belinostat (HDAC inhibitor) and 3-Deazaneplanocin A (HMT inhibitor) in combination with conventional treatment (Retinoic acid and Idarubicin). We demonstrated that the combined treatment used in the study had slightly higher effect on cell proliferation inhibition than conventional treatment. Also, enhanced treatment showed stronger effect on induction of apoptosis and on suppression of metabolism. Moreover, the treatment accelerated granulocytic cell differentiation and caused chromatin remodelling (increased H3K14 and H4 acetylation levels). In vitro and ex vivo models showed similar response to the treatment with different combinations of 3-Deazaneplanocin A, Belinostat, Retinoic acid, and Idarubicin. In conclusion, we suggest that 3-Deazaneplanocin A and Belinostat enhanced conventional acute promyelocytic leukemia treatment and could be considered for further investigations for clinical use.

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

“…Many combination therapy regimens have been used in clinical oncology treatment. 452,456,457 Furthermore, some novel combination strategies, such as combining HDAC inhibitors with epigenetic-targeted drugs, proteasome inhibitors, or immunotherapy, have also exhibited good therapeutic effects in preclinical studies. 453,[458][459][460] IDH1/2 inhibitors Isocitrate dehydrogenases (IDHs) include three subtypes (IDH1, IDH2, and IDH3) and are key enzymes that catalyze the conversion Fig.…”

Differentially Expressed Bone Marrow microRNAs Are Associated With Soluble HLA-G Bone Marrow Levels in Childhood Leukemia

“…The RREB-1 protein is a well-known repressor of HLA-G expression, interacting with the HLA-G gene at three different sites in the promoter region ( Flajollet et al, 2009 ). In addition, it is important to note that RREB-1 acts in a complex with other proteins, HDAC1, CtBP1/2, REST, EHMT1, ZEB1/2, and ZnF217, which are involved in chromatin remodeling and transcription machinery assembly ( Delcuve et al, 2012 ; Barroilhet et al, 2013 ; Ray et al, 2014 ; Vitkevičienė et al, 2019 ) and are also targets for these differentially expressed miRNAs. However, the role of hsa-miR-4488 at the RRE site is unclear, since hsa-miR-4488 regulates the expression of RREB1, which induces the downregulation of HLA-G expression by binding to the RRE site.…”

Genetic and Epigenetic Signatures in Acute Promyelocytic Leukemia Treatment and Molecular Remission

“…Cell lysates were prepared as described previously ( Vitkeviciene et al, 2019 ). Proteins were fractionated in 7.5–15% SDS-PAGE gradient electrophoresis gel and transferred on the PVDF membrane.…”