Gemcitabine (GEM) is one of the first-line drugs in the treatment of
gallbladder cancer (GBC), although the
therapeutic effect is not sustained due to resistance to the
drug over time.
Maslinic acid (MA) has been shown to inhibit
transcription factor nuclear factor-κB (NF-κB), resulting in the suppression of survival signaling. The authors of the present study investigated whether MA enhanced the antitumor activity of GEM in GBC. Anti-proliferative effects of MA, GEM and MA+GEM were assessed using the MTT assay. Apoptosis was assessed using
Annexin V and by western blot analysis of various mediators of apoptosis. Xenograft
tumors of EH-GB2 GBC cells were established in athymic nude mice and were monitored following treatment with MA, GEM and MA+GEM. Immunohistochemistry of the
tumors was used to examine various survival
proteins. MA inhibited the in vitro proliferation of various GBC cell lines and potentiated the apoptosis and cell invasion inhibition induced by GEM. Western blot analysis showed that the combination of MA and GEM inhibited constitutive NF-κB activation and NF-κB-regulated gene products, including
cyclin D1, Bcl-2, Bax, MMP-2 and MMP-9, to a greater extent. In vivo, the group that was treated with MA+GEM showed significant reductions in
tumor volume and a decreased expression of NF-κB-regulated gene products. In conclusion, the results suggest that MA potentiates the antitumor effects of GEM in human GBC cell lines by suppressing the activation of NF-κB and its dowstream gene products, which are involved in survival signaling.