Sorafenib and Lithium Chloride Combination Treatment Shows Promising Synergistic Effects in Human Glioblastoma Multiforme Cells in Vitro but Midkine Is not Implicated

Abstract

Objectives: The objectives of this study were to test the effects of the new combination treatment modality, sorafenib (SOR) and lithium chloride (LiCl) and to assess whether midkine (MK) protein has a role in any potential effects.

Methods: Monolayer and spheroid cultures of T98G human glioblastoma multiforme (GBM) cells were treated with LiCl and SOR (inhibition concentration 50 value = 100 mu M), or their combination, or were left untreated (control). Cell proliferation and apoptotic indices, the mechanism of action, and the levels of apoptotic and anti-apoptotic proteins were evaluated in monolayer cultures and ultrastructure was evaluated by transmission electron microscopy (TEM) in spheroid cultures after for 72 hours.

Results: All drug applications decreased cell numbers and increased the apoptotic index. The combination shows a synergistic effect. In the combination group, the decrease in cell numbers and the increase in the apoptotic index were significantly greater than with the individual drugs (P < 0.01). The combination treatment led to the greatest decreases in MRP-1 and p170 levels; but the greatest decreases in p-STAT-3, p-ERK (P < 0.05), p-AKT, p-GSK-3-beta (P < 0.01), EGFR (P < 0.01), NF-kappa-beta levels were with SOR alone, followed by the combination. The decreases in MK levels in the SOR and combination groups were similar (P = 0.06). Severe ultrastructural damage was more frequently observed in the combination group compared with the other groups.

Conclusions: These results suggest the possibility that the addition of LiCl to SOR could improve the prognosis in at least some patients who need both cancer and psychotherapy and indicate the need for further studies.