Fig. 6.

Combined inhibition of PI3Kβ and MLK3 effectively suppress glioblastoma xenograft growth in vivo. a Glioblastoma cells U-118 MG (5 × 10⁶ cells) were subcutaneously injected into the flank of Balb/C nude mice. Mice were intraperitoneally (i.p.) injected once daily for 7 days with vehicle, AZD6482 (30 mg/kg) and URMC-099 (3 mg/kg) alone or in combination. Measurement of tumor volumes started on the day of the first administration. a Representative photographs show the size of subcutaneous tumor xenografts from mice sacrificed after 36-day post-administration. b Tumor volumes from 12-day post-administration to the end of the experiment, and tumor weight of tumor xenografts after sacrifice in 36-day post-administration were measured. n = 6; statistical difference of tumor volumes was determined by One-way repeated measures ANOVA and Post Hoc multiple comparison Tukey HSD test, while difference of tumor weight was determined by One-way ANOVA and Post Hoc multiple comparison Tukey HSD test. *: p < 0.05. c Immunohistochemistry analysis of the phosphorylation of Akt, JNK and ERK in representative sections of tumor xenografts after sacrifice. Bar = 20 μm. d–f IHC staining scores of the phosphorylation of Akt, JNK and ERK in tumor sections. P values were determined by One-way ANOVA and Post Hoc multiple comparison Tukey HSD test. *: p < 0.05; **: p < 0.01. g Simplified schematic representation demonstrating a crosstalk between PI3Kβ and MLK3. Concurrent inhibition of these two molecules displayed synergistic anti-glioblastoma effects through inhibition of Akt, ERK, ROCK2 and Zyxin