Background
Sorafenib, a multiple-target-point kinase inhibitor, has been used as a standard treatment for advanced liver cancer and has shown therapeutic benefits. However, resistance often occurs, prompting the need for identification of synergizing agents. Celastrol is a major active ingredient of
Tripterygium wilfordii,
which can increase the antitumor effect of traditional antitumor drugs. This work focused on the sensitization of liver cancers in use of celastrol combined with sorafenib.
Material/Methods
The IC50 values of sorafenib and celastrol on cancer cells were determined through MTT assays. The effects of sorafenib on AKT signaling and VEGF levels in sorafenib-treated cancer cells were analyzed by Western blotting and ELISA, respectively. After combined treatment with celastrol and sorafenib, the survival rate of tumor cells was determined by MTT and clonogenic assays, and the apoptosis rate was also determined by flow cytometry. In addition, the
in vivo
antitumor activity of celastrol combined with sorafenib was evaluated in Hepa1-6 tumor-bearing mice.
Results
Sorafenib treatment induced the compensatory activation of the AKT pathway and autocrine VEGF in hepatoma cells, which could be reversed by celastrol. Furthermore, celastrol enhanced the growth inhibition and apoptosis induction of cancer cells by sorafenib both
in vitro
and
in vivo
and reduced the dosage of sorafenib needed.
Conclusions
Celastrol enhances the antitumor activity of sorafenib in HCC tumor cells by suppressing the AKT pathway and VEGF autocrine system.