Phenoxodiol Enhances the Antitumor Activity of Gemcitabine in Gallbladder Cancer Through Suppressing Akt/mTOR Pathway

Gallbladder cancer is the most common and aggressive type of biliary tract cancer with poor prognosis due to both its inability to be detected at an early stage and its poor sensitivity to conventional therapies. Gemcitabine has been more and more widely used for the treatment of gallbladder cancer; however, the response rate is not satisfactory. Phenoxodiol is an isoflavone analog with antitumor activity against a variety of cancers. In our current work, we examined the effect of phenoxodiol on gallbladder cancer cells and to determine whether phenoxodiol can enhance the antitumor activity of gemcitabine in gallbladder cancer. The combined treatment of phenoxodiol and gemcitabine was more effective at inhibiting cell proliferation than either chemotherapeutic agent treatment alone. Meanwhile, phenoxodiol arrests cell cycle progression in the G0–G1 phase. In addition, phenoxodiol and gemcitabine inhibit the phosphorylation of PI3K/Akt-signaling pathway as well as modulate the expression of apoptosis-relevant molecules. Furthermore, the antitumor effect of combination treatment with phenoxodiol and gemcitabine on gallbladder cancer was evaluated using a murine gallbladder cancer xenograft model and the results suggested that phenoxodiol enhanced the in vivo antitumor activity of gemcitabine. Taken together, our study suggested that the combination treatment with phenoxodiol and gemcitabine might offer optimal therapeutic benefits for patients with gallbladder cancer.