A potential strategy for high-grade gliomas: combination treatment with lithium chloride and BmK CT

Abstract

Therapies for high-grade gliomas (HHG) that have strong tendency of infiltration and resistance to chemotherapies are currently unavailable. Here, we report that lower-dose combination therapy of Buthus martensii Karsch (BmK) CT, a type of scorpion toxin peptide, and LiCl, clinically used as mood stabilizer, could synergistically inhibit the migration, invasion and proliferation of C6 glioma cells. The decreased invasiveness of C6 glioma cells was accompanied by inhibited activation, catalytic activity and/or expression of matrix metalloproteinase-2. Moreover, TOPfalsh luciferase reporter and immunofluorescence staining showed altered localization pattern of β-catenin at the leading edge of 2D scratch. Our results suggested that the combination treatment of lithium and BmK CT may constitute a novel and potential strategy for HHG therapy.

Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Akt pathway in gliomas

“…1A-C and 2A showed that LiCl treatment reduced outgrowth of astrocytic cell processes (which may be linked to an altered migratory capacity 27 ) and in conjunction with previous studies such as those by Nowicki et al, 24 imply that lithium may have potential therapeutic efficacy in glioma. AktX, a specific inhibitor of Akt phosphorylation, was used to treat U87MG ( Fig.…”

Lithium Chloride and Inhibition of Glycogen Synthase Kinase 3β as a Potential Therapy for Serous Ovarian Cancer

“…10,11 In addition, LiCl is associated with phosphorylation of a regulatory serine-9 on the N-terminal region, which is a principal regulator of GSK3A. 12 In vitro studies have demonstrated that treatment with LiCl can inhibit growth of endometrial cancers, 13 gliomas, 14 carcinoid tumors, 15 colorectal cancers, 16 and ovarian cancers. 17 Therapeutic serum levels for LiCl are 0.8 to 1.2 mEq/L (0.8Y1.2 mM), with lithium toxicity usually beginning at 1.5 to 2 mEq/L (1.5-2 mM).…”

Scorpion Peptides: Potential Use for New Drug Development

“…Unfortunately, the poor specificity of chemotherapeutic substances to render them less efficacious [125]. The ability of natural toxins to bind specifically to various cellular domains upholds new hope for anticancer drug development, like bombesin and bombesin-like toxins which have been used as drug motifs carriers with high specificity against tumoral cells [126][127][128][129][130]. This property is an attribute of chlorotoxin, a peptide extracted from the venom of Leiurus quinquestriatus hebraeus, which specifically binds to chloride-gated channels [107,[131][132][133] that are firmly involved in cancer cells mobility mechanism [134]; and impairs the in vitro glioma invasion [108][109][110].…”

“…The list of scorpion peptides exhibiting anti-proliferative and cytotoxic effects on tumor and malignant cells is expanding, and new substances are being continually added [126,[138][139][140][141][142].…”

“…Such findings will probably prompt the breaking down of immune tolerance to cancerous cells and improve cellular therapeutic strategies. Other peptides enhance the expression of P21 and caspases-3 proteins, members of the programmed cell death [141], or inhibit the expression or the activity of matrix metalloproteinase-2 and alter the -catenin localization [126].…”