Figure 1.

Combined treatment with BH3-mimetics (ABT263, GX15-070) and the mitochondrial matrix inhibitor Gamitrinib (G-TPP) results in a synergistic antiproliferative effect across a wide spectrum of human glioma and other solid cancer cells. A, 3-dimensional representation of the chemical structures of G-TPP, ABT263 and GX15-070. B, U87MG, U87-EGFRvIII, LN229, T98G established glioblastoma cell lines, GS9-6 and NCH644 glioma stem-like cells, A375 melanoma and MDA-MB-468 breast cancer cells were treated as indicated with G-TPP, ABT263, GX15-070 or the respective drug combinations under serum starvation (1.5% FBS). After 72h of treatment, MTT assays were performed. Column: mean. Error bar: standard error of the mean (SEM). Statistical analysis was performed and p-values were calculated. C–D, U251 glioblastoma cells were treated for 72 hours with ABT263 (C), GX15-070 (D), G-TPP or the combination as indicated. Normalized isobolograms were calculated using the CompuSyn software (ComboSyn, Inc., Paramus, NJ, U.S.A.). Data points located on the line indicate an additive drug-drug interaction. Data points located below the line indicate a synergistic drug-drug interaction and data points above the line indicate an antagonistic drug-drug interaction. E–F, T98G and U87MG cells were treated as indicated with G-TPP, WEHI-539, ABT199, A-1210477 or the respective drug combinations under serum starvation (1.5% FBS). After 72h of treatment, CellTiter Glo® assays were performed. Column: mean. Error bar: standard deviation (SD). Statistical analysis was performed and p-values were calculated. G, Representative microphotographs of T98G glioblastoma cells after 24 h of treatment with G-TPP, ABT263 or both. Morphological changes such as a rounding of cells and the formation of blebs (arrowheads) are commonly seen after treatment with both agents.