Inhibiting stemness and invasion property of glioblastoma tumorsphere by a newly designed biguanide

Abstract

Glioblastoma (GBM) is a lethal disease with limited survival in spite of recent therapeutic progress and a new strategy against the disease is being required. Recently, the effect of biguanide derived agents are being suggested as new groups of target in the treatment of malignant tumors and their effect against the tumorsphere (TS) were reported. In this study, I assessed effects of a newly developed biguanide, HL156A, on the properties of glioblastoma tumorsphere (GBM-TS) and survival of orthotopic xenograft animals, to assess the feasibility of this agent, alone or combined with conventional therapeutic agent temozolomide (TMZ), in the treatment of GBM. HL156A, alone and combined with TMZ, exhibited an inhibitory effect on the stemness of GBM-TS, proven by the neurosphere formation assay and the assessment of stemness marker expression, without affecting viability of cells. The invasive property of GBM-TS were inhibited most significantly by the combination treatment, compared with the control and HL156A or TMZ alone-treated groups in 3-dimentional collagen matrix invasion assay. The combination treatment repressed epithelial-mesenchymal transition (EMT) related gene expression. Gene ontology class comparison of TMZ and combination treatment group revealed altered expression of gene sets involving cellular adhesion and migration. The combined treatment of HL156A and TMZ showed survival benefits in the orthotopic xenograft mouse model. Targeting of GBM-TSs by the combination of HL156A and TMZ, through the inhibition of stemness and invasion properties of GBM- TS, can be a novel candidate for the treatment of GBM.