INTRODUCTION: This study was an investigation of the mechanisms of sorafenib (SOR) and lithium chloride (LiCl), which cause apoptosis, in the acute promyelocytic leukemia (APL) HL-60 cell line.
METHODS: HL-60 cells were treated with 100 µM of SOR, LiCl, and a combination of the 2 drugs, and a control group was not treated. Cells were collected after a period of 24, 48, and 72 hours, and cell proliferation and the apoptotic index were assessed with a hemocytometer and flow cytometry analysis. The level of caspase-3, phospho-glycogen synthase kinase-3 beta (p-GSK-3β), phospho-protein kinase B (p-AKT), phospho-extracellular-signal-regulated kinase (p-ERK), p38, phospho-c-Jun (p-c-Jun), and phospho-inhibitor kappa B (p-IκBα) were analyzed using the enzyme-linked immunosorbent assay method. The effects of the drugs on cell ultrastructure were evaluated with a transmission electron microscope (TEM).
RESULTS: Single and combination drug administration decreased cell proliferation and increased the apoptosis rate (p<0.01 for both). The increase in apoptosis in the SOR+LiCl group was greater than that of the SOR group (p<0.01); however, there was no significant increase compared with the LiCl group. While both drugs increased the caspase-3 level (p<0.01 for both), LiCl increased caspase-3 activity more than SOR. Although p-GSK-3β levels decreased in the SOR group (p<0.01), levels increased in the LiCl group (p>0.05). Combined drug administration decreased the level of p-AKT and p38 (p<0.01 for both); however, it did not significantly affect the level of p-ERK, p-IκBα, or p-c-Jun (p>0.05). TEM examination revealed severe lytic cytoplasmic damage and apoptotic morphology, an indication of apoptosis.
DISCUSSION AND CONCLUSION: The results of this study demonstrated that in human APL cells treated with SOR and LiCl, increased apoptosis led to a decrease in tumor cells. This combination may become a preferred drug alternative for patients with APL and a mood disorder.