title: Enhanced sensitivity to sorafenib by inhibition of Akt1 expression in human renal cell carcinoma ACHN cells both in vitro and in vivo.
abstract: To investigate whether antitumor activity of sorafenib, a potential molecular-targeted agent against RCC is enhanced by silencing Akt1 in a human RCC ACHN model. We established ACHN in which the expression vector containing short hairpin RNA targeting Akt1 was introduced (ACHN/sh-Akt1). Changes in several phenotypes of ACHN/sh-Akt1 following treatment with sorafenib were compared with those of ACHN transfected with control vector alone (ACHN/C) both in vitro and in vivo. When cultured in the standard medium, there was no significant difference in the in vitro growth pattern between ACHN/sh-Akt1 and ACHN/C; however, compared with ACHN/C, ACHN/sh-Akt1 showed a significantly higher sensitivity to sorafenib. Furthermore, treatment with Akt1 inhibitor, A-674563 also resulted in the significantly enhanced sensitivity of parental ACHN to sorafenib. Treatment of ACHN/sh-Akt1 with sorafenib, but not that of ACHN/C, induced marked downregulation of antiapoptotic proteins, including Bcl-2, Bcl-xL, and c-Myc. In vivo administration of sorafenib resulted in the significant growth inhibition of ACHN/sh-Akt1 tumor compared with that of ACHN/C tumor, and despite the lack of Ki-67 labeling index between ACHN/sh-Akt1 and ACHN/C tumors, apoptotic index in ACHN/sh-Akt1 tumor in mice treated with sorafenib was significantly greater than that in ACHN/C tumor. These findings suggest that combined treatment with Akt1 inhibitor and sorafenib could be a promising therapeutic approach for patients with advanced RCC.
authors: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Hiromoto
authors: H
authors: Tei
authors: Hideaki
authors: H
authors: Miyake
authors: Masato
authors: M
authors: Fujisawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt