Camptothecin improves sorafenib sensitivity by inhibiting Nrf2-ARE pathway in hepatocellular carcinoma

Abstract

Sorafenib is a targeted drug for hepatocellular carci- noma (HCC), however, its efficacy is limited. Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to sorafenib resistance. The present study investigated camptothecin (CPT) as a Nrf2 inhibitor to sensitize HCC to sorafenib. The effect of CPT on sorafenib sensitivity in HCC was assessed in vivo using H22 mice model (n=32) and VX2 rabbit models (n=32), which were sorted into four treatment groups. The expression levels of Nrf2, its downstream genes, including heme oxygenases-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), and the epithelial-mesenchymal transition markers Snail and N-cadherin in tumors were determined using immunohisto- chemical staining and western blotting. Magnetic resonance imaging was used to monitor changes in tumor microcirculation and activity before and after treatment. Mouse body weights, liver and kidney function were monitored to evaluate the safety of combined therapy. The results revealed that the mean tumor size of the combined group was significantly smaller than that of sorafenib group for both models. The expression levels of Nrf2, heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, Snail, and N-cadherin in the sorafenib group were significantly higher than control group (P<0.05). However, the expression levels of these genes were decreased in the combined group (P<0.05). Microcirculation perfusion and tumor activity in the combined group were also lower than sorafenib group. There were no significant differences in mouse body weight or liver and kidney function among the four groups. In summary, CPT is a Nrf2 inhibitor that could enhance the efficacy of sorafenib against HCC.