Luteolin induces myelodysplastic syndromederived cell apoptosis via the p53dependent mitochondrial signaling pathway mediated by reactive oxygen species
Luteolin, a common dietary flavonoid, induces the apoptosis of cells in several types of cancer. However, its role in myelodysplastic syndrome (MDS) and the potential underlying mechanisms remain to be elucidated. To evaluate the potential benefit and underlying mechanisms of luteolin in MDS cells, the viability of SKM1 cells and primary bone marrow (PBM) mononuclear cells from patients with intermediate or highrisk MDS were assessed using a Cell Counting Kit8 assay. The apoptotic features of cell morphology were assessed using WrightGiemsa staining, DNA fragmentation was analyzed by agarose gel electrophoresis, and the extent of apoptosis was quantified by flow cytometry (FCM). Reactive oxygen species (ROS) were measured by FCM with 2,7dichlorodihydrofluorescein diacetate staining and mitochondrial membrane potential (ΔΨm) was determined using 5,5',6,6'tetrachloro1,1',3,3'tetraethylbenzimidazolylcarbocyanine iodide staining. Caspase activity was detected using a fluorometric protease assay. Furthermore, the effects of luteolin on the expression of apoptosisrelated proteins were analyzed using western blot analysis. The resulting data revealed that luteolin significantly inhibited the proliferation of SKM1 cells in vitro, and its half maximal inhibitory concentration was 139.41 µM at 24 h and 23.95 µM at 72 h. Luteolin also markedly inhibited the proliferation of mononuclear cells from patients with intermediate or highrisk MDS. Luteolin suppressed cell proliferation, mainly as a result of the induction of apoptosis, as demonstrated by typical apoptotic morphological features, the ladder pattern of genomic DNA fragmentation, and the results of FCM using Annexin VFITC/PI double staining. It was also found that shortterm exposure of SKM1 cells to luteolin led to a marked increase in the accumulation of ROS. The increased intracellular level of ROS appeared to induce the activation of p53 and elevate the Bcell lymphoma 2 (Bcl2)associated X protein/Bcl2 ratio, which modulates ΔΨm and triggers the release of cytochrome c, and may increase the activities of apoptotic protease activating factor 1, caspase3, 8 and 9 to further trigger the destruction of structural and specific proteins and thereby cell apoptosis. Notably, the inhibition of ROS generation by the antioxidant NacetylLcysteine significantly attenuated the luteolininduced loss of ΔΨm and activities of caspase3, 8 and 9. These data suggested that luteolin exerts its proapoptotic action partly through the p53dependent mitochondrial signaling pathway mediated by intracellular ROS, which provides a promising therapeutic candidate for patients with MDS.
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Document Type: Research Article
Affiliations: Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou, Jiangsu 213003, P.R. China
Publication date: January 1, 2018
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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