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: Hiromoto Tei, Hideaki Miyake, Masato Fujisawa
• Journal: Human cell (Hum Cell) Vol. 28 Issue 3 Pg. 114-21 (Jul 2015) ISSN: 1749-0774 [Electronic] Japan
• PMID: 25862630 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• Niacinamide
• Sorafenib
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Carcinoma, Renal Cell (genetics, pathology)
• Cell Proliferation (drug effects, genetics)
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Gene Silencing (drug effects)
• Humans
• Kidney Neoplasms (genetics, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics)
• Sorafenib
• Tumor Cells, Cultured