Knockout of ADAM10 enhances sorafenib antitumor activity of hepatocellular carcinoma in vitro and in vivo.

Abstract

Sorafenib (SOR), a vascular endothelial growth factor receptor (VEGFR) inhibitor, is in wide clinical use for the treatment and prevention of liver cancer. However, extended SOR administration for hepatocellular carcinoma (HCC) induces drug resistance thereby limiting its efficacy and highlighting the need for improved therapeutic strategies. It has previously been demonstrated that knockout of a disintegrin and metalloproteinase10 (ADAM10) via siRNA induced cancer apoptosis and decreased chemotherapy drug resistance. However, whether knockout of ADAM10 is able to decrease SOR resistance remains to be determined. Therefore, in the present study, the effect of siRNA-ADAM10 in combination with SOR was analyzed in HCC cell lines (HepG2) by inhibiting tumor growth and simultaneously reducing doses of SOR. Cell proliferation, apoptosis, migration, invasion and involvement in receptor signaling were determined after siRNA-ADAM10 was applied in combination with SOR treatment. Tumor growth ability in nude mice was also detected. The results showed that siRNA-ADAM10 in combination with SOR treatment in HCC cancer cells significantly suppressed proliferation, migration and invasion, and induced tumor apoptosis invitro, and suppressed tumor growth invivo. In addition, the results showed that knockout of ADAM10 by siRNA inhibited the constitutive phosphorylation of PI3K and AKT, which may contribute to the reduction of SOR resistance. Collectively, our experimental results indicate that knockout of ADAM10 by siRNA increased the SOR antitumor activity of liver cancer invitro and invivo, and that this additive combination is a promising drug candidate for treatment of HCC.