Mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by valproic acid combined with temsirolimus.
10.7534/j.issn.1009-2137.2013.06.014
- Author:
Zhong ZHENG
1
;
Yan ZHAO
1
;
Li-Hua DONG
1
;
Li WANG
1
;
Shu CHENG
2
;
Wei-Li ZHAO
1
Author Information
1. Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, State Key Laboratory of Medical Genomics, Shanghai 200025, China.
2. Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, State Key Laboratory of Medical Genomics, Shanghai 200025, China. E-mail: orenge@medmail.com.cn.
- Publication Type:Journal Article
- MeSH:
Autophagy;
drug effects;
Cell Cycle Checkpoints;
drug effects;
Cell Line, Tumor;
Cell Proliferation;
drug effects;
Epigenesis, Genetic;
Histone Deacetylase 1;
metabolism;
Histone Deacetylases;
metabolism;
Humans;
Lymphoma, Large B-Cell, Diffuse;
pathology;
Microtubule-Associated Proteins;
metabolism;
Sirolimus;
administration & dosage;
analogs & derivatives;
pharmacology;
Valproic Acid;
administration & dosage;
pharmacology
- From:
Journal of Experimental Hematology
2013;21(6):1441-1447
- CountryChina
- Language:Chinese
-
Abstract:
The aim of this study was to illustrate the mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by histone deacetylase inhibitor valproic acid (VPA) combined with mTOR inhibitor temsirolimus (TEM). MTT assay and Wright's stain were used to assess cell growth inhibition and to detect the cell morphological changes respectively. The cell apoptosis, cell cycle and cell autophagy were determined by flow cytometry. Ultrastructure changes were confirmed by electron microscopy. Protein changes were detected by Western blot. The results showed that both VPA and TEM alone inhibited cell proliferation and the effect was more obvious in the combination group. VPA combined with TEM induced cell arrest in G0/G1 phase and upregulated the expression of autophagy-related protein LC3, without cell apoptosis. Moreover, typical autophagosomes were observed, further confirming the presence of autophagy. Western blot showed the changes of proteins involved in autophagy signaling pathway. VPA decreased HDAC1 and HDAC3 expression and increased histone acetylation, suggesting that VPA also affected lymphoma cell proliferation through epigenetic modification. It is concluded that the combined treatment of VPA and TEM induces cell cycle arrest and cell autophagy, which provides a new clue for their clinical application in diffuse large B-cell lymphoma.
