title: Sorafenib and lithium chloride combination treatment shows promising synergistic effects in human glioblastoma multiforme cells in vitro but midkine is not implicated.
abstract: OBJECTIVE
  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 μM), 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-β 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.
authors: Pulat Akιn
authors: PA
authors: Sabancι
authors: Mine
authors: M
authors: Ergüven
authors: Nuray
authors: N
authors: Yazιhan
authors: Esin
authors: E
authors: Aktaş
authors: Yavuz
authors: Y
authors: Aras
authors: Erdinç
authors: E
authors: Civelek
authors: Aydιn
authors: A
authors: Aydoseli
authors: Murat
authors: M
authors: Imer
authors: Mehmet
authors: M
authors: Gürtekin
authors: Ayhan
authors: A
authors: Bilir
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000648:ultrastructure; D006801:Humans; D018021:Lithium Chloride / Q000627:therapeutic use*; D000078792:Midkine; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D016207:Cytokines; D010671:Phenylurea Compounds; D000078792:Midkine; D009536:Niacinamide; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; D018021:Lithium Chloride
keywords: Combination chemotherapy,; Glioblastoma,; Lithium chloride,; Midkine,; Sorafenib