The Mechanism Of Ascorbic Acid Killing Myelodysplastic Syndrome Cells

Objectives Intravenous ascorbic acid(ascorbate,Vitamin C)could result in high plasma concentrations which could kill some tumor cells.Myelodysplastic syndromes(MDS),previously called pre-leukemic,represents a group of myeloid clonal disorders originating from hematopoietic stem cells with a high risk of transformation to acute myeloid leukemia.Because most patients with MDS are older,they often can’t tolerate high-intensity chemotherapy and allogeneic stem cell transplantion.Even worse,the recommended hypomethylating agents for such patients also have limited curative effect because of the side effects and resistance.Therefore,whether ascorbic acid,a safe and inexpensive natural compound,can be used to treat MDS alone or synerging with other regimens,such as hypomethylating agents,has attracted great attention and interest from hematologists and basic science researchers.This study intended to investigate whether ascorbic acid monotherapy or in combination with descitabine could kill the MDS cells and further explore its mechanism.Methods 1.SKM-1 and MUTZ-1 cells(human MDS cell lines)were incubated with ascorbic acid of different concentrations,then the proliferation activity of cell lines aboved was detected by CCK-8 assay.The level of intracellular ROS and Labile iron pool(LIP),cell cycle and apoptosis of SKM-1 and MUTZ-1 cells were detected by flow cytometry.2.The control group,ascorbic acid monotherapy group,desitabine monotherapy group and the combination group which included ascorbic acid and desitabine were set up,then the proliferation activity and apoptosis were detected in each group separately.Results 1.The proliferation activity of both SKM-1 and MUTZ-1 cells treated with high-dose ascorbic acid was inhibited.With the increased concentration of ascorbic acid,the level of intracellular ROS was increased and the proportion of cells which were blocked in G2 phase increased.Less surviving cells,more apoptotic cells were detected in experimental group.Nevertheless,the level of LIP wasn’t elevated by ascorbic acid as we expected.2.Both SKM-1 and MUTZ-1 cells in the combination group which were treated with ascorbic acid and decitabine owned decreased proliferation activity and accelerated apoptosis when compared with the ascorbic acid monotherapy group and desitabine monotherapy group.Conclusion 1.High-dose ascorbic acid showed highly selective cytotoxicity targeting MDS cancer cells which could inhibit their proliferation activity and induce their apoptosis by elaluating the level of intracellular ROS.The evaluated ROS level may result in the high redox stress so that the cell cycle was arrested in G2 phase.2.High-dose ascorbic acid synerging with decitabine inhibited proliferation and induced apoptosis of MDS tumor cells.