Synergistic induction of apoptosis in HeLa cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitor SAHA.

Proteasome inhibitors and histone deacetylase (HDAC) inhibitors are two promising groups of anti-cancer agents. In this study, we examined the apoptotic effects of the proteasome inhibitor bortezomib and HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in human cervical carcinoma HeLa cells. Compared to treatment with bortezomib or SAHA alone, co-exposure with these two agents synergistically resulted in the massive apoptosis of HeLa cells, consistent with a significant increase in caspase-3 activation. We then investigated the mechanisms underlying this effect. The combination of bortezomib and SAHA caused an increase in the ratio of bax/bcl-2 expression, inhibited the nuclear transportation of NF-κB, and down-regulated Akt expression and phosphorylation in HeLa cells. In conclusion, bortezomib and SAHA cooperatively stimulate apoptosis in HeLa cells through the inhibition of several cyto-protective signalling pathways. This is the first report of synergistic apoptotic effect achieved with a proteasome inhibitor and HDAC inhibitor in HeLa cells. Thus, the results build the framework for clinical trials using combined proteasome and HDAC inhibition in the treatment of human cervical carcinoma.