Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

Figure 4

Potent antitumor effects of the everolimus/patupilone combination in in vivo models of HCC. Hep3B cells (3 × 10⁶ cells) were inoculated into nude mice by subcutaneous injection. Drug treatments were started on day 20 after inoculation. Mice received administration of drugs for two weeks (black arrow: patupilone i.p. injection; red arrow: everolimus orally given). (a) Treatment of mice with everolimus, patupilone, or combination suppressed tumor growth in established xenografts of Hep3B. Tumor growth was monitored twice weekly. Arrows indicated time of drug administration. The in vivo antitumor activity of everolimus/patupilone combination was more significant than either agent alone (𝑛=10 per group, *𝑃<0.05, **𝑃<0.01, ***𝑃<0.001 versus vehicle group). (b) Tumor weight of Hep3B xenografts in each group. The tumor weight of everolimus/patupilone combination group was significantly reduced (𝑛=10 per group, **𝑃<0.01 versus vehicle group). (c) The mTOR signaling in HCC cells was not further suppressed by the everolimus/patupilone combination treatment in Hep3B xenograft. Tumor xenografts were harvested, fixed, and stained for pi-mTOR and pi-S6 by immunohistochemistry. Representative images (400x magnification) were shown. Quantitation of pi-mTOR and pi-S6 staining using immunohistochemistry scoring was shown in (B) (𝑛=10 per group, *𝑃<0.05, **𝑃<0.01, ***𝑃<0.001 versus vehicle group).

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