Effects of Sodium Valproate on Proliferation and Apoptosis of Human Myelodysplastic Syndromes Cell Line MUTZ-1.

OBJECTIVE: Myelodysplastic syndromes (MDS) are a heterogeneous group with the expansion of a malignant clone. No satisfactory treatment for MDS is available. Sodium valproate (VPA), can induce G₀–G₁ phase arrest and cell apoptosis, inhibit proliferation of tumor cells in vitro significantly. The effects and possible mechanism of VPA on MUTZ-1 cell line of MDS were studied in this experiment.

METHODS: Cell proliferation was determined by MTT assay. Apoptotic morphological features were observed under microscope and transmission electronmicroscope. Cell apoptosis and cell cycle were analyzed by flow cytometry (FCM). The expression of p21^WAF1(cyclin-dependent kinase inbihitor) was detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis.

RESULTS: VPA could inhibit the proliferation of MUTZ-1 cells in dose-and time-dependent manners. The typical apoptotic morphological features appeared in cells treated with 4 mmol/L VPA for 72 hours. Condensation of cells and nuclear chromatin, disintegration of nuclear chromatin, and apoptotic body could be observed under microscope. Aggregation and margination of apoptotic nuclear chromatin, cytoplasm condensation, and irregular chromatin masses could be observed under transmission electronmicroscope. The percentage of apoptotic cells which were treated with 1,2 and 4 mmol/L VPA for 72 hours increased from 1.39% to 2.18%, 16.03%, 22.02%, and cell cycle arrest at G₀–G₁ phase could be caused by VPA as shown by FCM. The expression level of p21^WAF1 mRNA and p21^WAF1 protein were up-regulated in a dose dependent manner in MUTZ-1 treated with VPA for 72 hours (P<0.05).

CONCLUSION: VPA induced a G₀–G₁ cell cycle arrest and have an effect on proliferation and apoptosis of MUTZ-1 cells in vitro. The mechanism may be associated with the up-regulation of p21^WAF1.