Decitabine shows synergistic effects with arsenic trioxide against myelodysplastic syndrome cells via endoplasmic reticulum stress-related apoptosis

Abstract

Most of the International Prognostic Scoring System (IPSS) high-risk patients with myelodysplastic syndrome partly responded to hypomethylating therapy even with transient remission, while arsenic trioxide (ATO) had partial effect in patients with MDS. Therefore, we sought to investigate the effects and possible mechanisms of the combination of ATO and decitabine (DAC) in MDS cells. In our study, the MUTZ-1 and SKM-1 cells were treated with ATO, DAC or both. Cell viability, cell apoptosis, levels of reactive oxygen species (ROS) and expressions of the endoplasmicreticulum (ER) stress-associated genes and proteins were examined. Results showed the combination of ATO and DAC synergistically inhibited the proliferation and induced apoptosis of MDS cells. Through the RNA-sequence and GSEA gene function analysis, ER stress-related pathway played an important role in apoptosis of MDS cells induced by the combination of ATO and DAC. ER stress-related genes DNA damage inducible transcript 3, GRP78, and activating transcription factor-6 were significantly highly expressed in combination group than those in single agent groups; proteins were confirmed by western blot. The levels of ROS significantly increased in the combination group. Furthermore, the apoptosis of (ATO+DAC) group MDS cells could be partially reversed by antioxidant agent N-acetylcysteine, accompanied by decreased expression of intracellular ROS and ER stress-related genes. These results suggested that the combination of ATO and DAC synergistically induced the apoptosis of MDS cells by increased ROS-related ER stress in MDS cells.

TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

“…ATO is widely reported to be able to degrade and thus inhibit the oncogenic function of mutated p53 [137]; ATO, in fact, suppresses cancer cell growth by targeting mutated p53, for degradation by Pirh2-pathway [138]. Furthermore, it was shown that the combination of ATO and DAC synergistically induces the apoptosis of MDS cells, increasing the levels of reactive oxygen species and inducing the endoplasmic reticulum stress [139]. In TP53-mutated MDS, the potential of DAC plus ATO combination will be evaluated considering the RFS improving and the ability to thoroughly eliminate the TP53-mutated subclone.…”

UNC13B Promote Arsenic Trioxide Resistance in Chronic Lymphoid Leukemia Through Mitochondria Quality Control

“…ATO has been used in combination with other drugs in a variety of cancers, such as T-cell acute lymphoblastic leukemia ( 16 ), myelodysplastic syndromes ( 17 ), idiopathic thrombocytopenic purpura ( 18 ), acute myeloid leukemia ( 19 ), and multiple myeloma ( 20 ); moreover, it has been used in patients with both newly diagnosed and refractory or relapsed cancers. ATO shows a certain degree of curative effect, and so our group has been examining ATO resistance in leukemia.…”

Hematopoietic Stem Cells (HSC) and Granulocyte Macrophage Progenitors (GMP) are the Oxidative Stress Targets in Low/Intermediate-1 Risk Myelodysplastic Syndromes

“…Also clinical reports of arsenic trioxide (ATO) combined with decitabine (DAC) showed an increase of high-risk MDS cells apoptosis via ROS production [ 47 ]. It has been reported that patients with hematological malignancies, including MDS, are vitamin-C deficient [ 48 ].…”