title: 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 metalloproteinase 10 (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 in vitro, and suppressed tumor growth in vivo. 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 in vitro and in vivo, and that this additive combination is a promising drug candidate for treatment of HCC.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Songyang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Bai
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Liu
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D055786:Gene Knockout Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism*; D000077157:Sorafenib
chemical_list: D008565:Membrane Proteins; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse