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  • Title: [Valproic acid induced intracellular GSH-redox imbalance and apoptosis of leukemic cells resistant to dexamethasone and doxorubicin].
    Author: Liu H, Fu RY, Liao QK, Li FY, Zhu YP, Gao J, Mao YQ.
    Journal: Sichuan Da Xue Xue Bao Yi Xue Ban; 2009 Jan; 40(1):133-7. PubMed ID: 19292063.
    Abstract:
    OBJECTIVE: To investigate the anti-neoplastic effects of Valproic acid (VPA) on leukemic cells, especially drug-resistant lines, and to investigate whether modulation of GSH-redox status is involved in VPA-induced apoptosis. METHODS: After the treatment of VPA at various concentrations for indicated times, cellular proliferation of the Jurkat, CEM, HL-60, K562, K562/AO2 cells were evaluated via MTT assay; and the activities of Caspase-3, Caspase-8 and Caspase-9 were quantitatively analyzed by colorimetric assay. The morphological change and cell cycle distribution were also examined on Jurkat (Dexamethasone-resistant) and K562/AO2 (Doxorubicin-resistant) cell lines. The levels of intracellular glutathione/glutathione disulfide (GSH/GSSG) and the activities of the typical antioxidant enzymes, i.e., glutathione reductase (GSH-Rd) and glutathione peroxidase (GSH-Px), were measured on cell lysates of Jurkat and K562/AO2 cell lines prior to and after VPA treatment. Apoptosis rates of Jurkat and K562/AO2 cells treated with VPA along or in combination with N-acety-l-cysteine (NAC), catalase (CAT) or DL-buthionine-(S,R)-sulfoximine (BSO) were determined by Annexin V/propidium iodide (PI) staining with flow cytometry analysis. RESULTS: At concentrations comparable with that achieved at clinical settings, VPA inhibited cell proliferation, activated Caspase-3, 8, and 9, and induced cell cycle arrest in Jurkat and K562/AO2. A rapid decrease in GSH-Rd and GSH-Px activities and GSH content in Jurkat and K562/AO2 were detected after VPA treatment. Co-administration of NAC or CAT attenuated VPA-induced apoptosis. CONCLUSION: VPA inhibit cell proliferation, induce cell cycle arrest and apoptosis in drug-resistant leukemic cells. Apoptosis correlates with down-regulation of intracellular GSH and disruption of intracellular GSH-redox balance, possibly through inhibition of glutathione reductase and glutathione peroxidase.
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