Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of
cancer. However, many solid
cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with
Oridonin, a bioactive molecules derived from
Traditional Chinese Medicine in
hepatocellular carcinoma (HCC) cells. Our results showed that
Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC
cancer stem-like cells. Moreover,
Oridonin dose-dependently inhibited the expression of several
anti-apoptotic proteins, such as Bcl-2, Mcl-1, and x-linked inhibitor of apoptosis (xIAP) in HCC cells. Cell fractionation and western blotting analysis showed that the enhancement of apoptosis by
Oridonin was associated with
cytochrome c release, activation of
caspase-9, -3 and cleavage of PARP, indicating the activation of mitochondrial apoptosis pathway. Altogether, our findings demonstrate that
Oridonin may be used to effectively enhance the sensitivity of BET inhibitors in HCC
therapy via downregulation of the expression of multiple
anti-apoptotic proteins.