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Enhanced sensitivity to sorafenib by inhibition of Akt1 expression in human renal cell carcinoma ACHN cells both in vitro and in vivo

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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.

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Authors and Affiliations

  1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Hiromoto Tei, Hideaki Miyake & Masato Fujisawa

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  1. Hiromoto Tei
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  2. Hideaki Miyake
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  3. Masato Fujisawa
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Correspondence to Hideaki Miyake.

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Tei, H., Miyake, H. & Fujisawa, M. Enhanced sensitivity to sorafenib by inhibition of Akt1 expression in human renal cell carcinoma ACHN cells both in vitro and in vivo. Human Cell 28, 114–121 (2015). https://doi.org/10.1007/s13577-015-0112-8

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  • DOI: https://doi.org/10.1007/s13577-015-0112-8

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