We have also found that statins induce selleck compound apoptosis by activation of caspase-3 through inhibition of GGPP biosynthesis. It has been reported that statins inhibit prenylation of small G proteins by suppressing the production of GGPP [4, 8]. Lovastatin is known to inhibit the mevalonic acid and MAPK pathways, thereby inducing apoptosis [9, 10]. It has been reported that the mechanism of action is inhibition of GGPP biosynthesis [10, 11]. These findings suggest that statins induce apoptosis by activation of caspase-3 through suppression

of GGPP biosynthesis. GGPP is an important membrane-anchoring molecule of Ras protein. A shortage of GGPP facilitates dissociation of Ras from the inner surface of the membrane, and decreases the Ras-mediated growth signal, thereby inhibiting cellular proliferation [12, 13]. Our results clearly demonstrate that statins induce a decrease in ERK1/2 and Akt activation of Ras downstream, selleck products but the activation of JNK1/2 was not altered. We previously reported that mevastatin induces a decrease in phosphorylated ERK [3]. We also demonstrated that fluvastatin and simvastatin decrease the activation of ERK1/2 Akt [4]. These findings are in agreement with the results of the present study and indicate that

statins induce apoptosis via suppression of Ras/ERK and Ras/Akt pathways in our experimental model (Figure 5). Figure 5 Schematic representation of interacellular effects of statins in C6 glioma cells. As described above, statins are known to affect the

functions of Ras by inhibiting prenylation through the inhibition of GGPP synthesis; this enables localization of Ras at the plasma membrane [14, 15]. Ras is involved in the activation of the MEK/ERK and PI3K/Akt pathways [14, 16], suggesting the mechanism of action of statins. The treatment of C6 glioma cells with 5 μM mevastatin, 5 μM fluvastatin or 10 μM simvastatin for 72 h in vitro inhibited GGPP synthesis. Megestrol Acetate We also found that the treatment of C6 glioma cells with 2.5 μM mevastatin, 1 μM fluvastatin or 5 μM simvastatin for 72 h inhibited cell proliferation. The peak plasma concentrations of fluvastatin or simvastatin achieved with standard doses were ≤ 1 μM or 2.7 μM, respectively [17, 18]. It has been reported that peak plasma concentration of fluvastatin achieved with high dose were ≤ 2 μM [19]. These findings indicate that 2 μM and 2.5 μM of fluvastatin and simvastatin, respectively, are within the peak plasma values of fluvastatin or simvastatin that are likely to be achieved in vivo. In addition, we found that 2.5 μM fluvastatin induced the apoptosis. Therefore, fluvastatin may be Selleckchem JNK-IN-8 potentially useful as anti-cancer agents in the treatment of glioblastoma. Conclusion In conclusion, these results provide evidence of the specific molecular pathways via which statins induce apoptosis by increasing the activation of caspase-3 through inhibition of Ras/ERK and Ras/Akt pathways.