Increased effects of 2,5-dimethylcelecoxib on sensitivity of hepatocellular carcinoma cells to sorafenib via CYP3A5 expression and activation of AMPK.

As the occurrence and development of HCC are often accompanied by inflammation, the combination of sorafenib with other therapeutic drugs, especially anti-inflammatory drugs, is one of the directions to be explored at present. Our previous research has been focused on the anti-inflammatory drug 2,5-dimethylcelecoxib (DMC), whether DMC combined with sorafenib could elevate the effect of inhibiting HCC deserves further exploration. In this study, we found that DMC induced CYP3A5 expression in HCC cells in a time-dependent and concentration dependent manner. We observed that sorafenib inhibited CYP3A5 expression in liver cancer cells, and activated the phosphorylation of Akt. Upregulated CYP3A5 and DMC treatment enhanced the ability of sorafenib to inhibit migration. The combination of DMC with sorafenib had a synergistic effect of enhancing drug sensitivity (CI < 1), meanwhile, inhibited the proliferation and promoted apoptosis of HCC. Activation of the AMPK pathway and inhibition of the PI3K/Akt pathway were observed in cells treated with DMC in combination with sorafenib and could be reverted by an AMPK pathway inhibitor. Our findings suggest that DMC induces CYP3A5 expression and enhances the anticancer effect of sorafenib by activating AMPK, which would be a novel strategy for drug combination to prevent drug resistance.