Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: Implication of c-Src and its inhibitor

  • Authors:
    • Yasuto Ueda
    • Tadashi Igishi
    • Kiyoshi Hashimoto
    • Hisashi Suyama
    • Kunio Araki
    • Takashi Sumikawa
    • Kenichi Takeda
    • Hirofumi Nakazaki
    • Keiji Matsunami
    • Masahiro Kodani
    • Yasushi Shigeoka
    • Shingo Matsumoto
    • Eiji Shimizu
  • View Affiliations

  • Published online on: March 1, 2009     https://doi.org/10.3892/ijo_00000195
  • Pages: 689-696
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Abstract

Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.

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March 2009
Volume 34 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Ueda Y, Igishi T, Hashimoto K, Suyama H, Araki K, Sumikawa T, Takeda K, Nakazaki H, Matsunami K, Kodani M, Kodani M, et al: Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: Implication of c-Src and its inhibitor. Int J Oncol 34: 689-696, 2009
APA
Ueda, Y., Igishi, T., Hashimoto, K., Suyama, H., Araki, K., Sumikawa, T. ... Shimizu, E. (2009). Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: Implication of c-Src and its inhibitor. International Journal of Oncology, 34, 689-696. https://doi.org/10.3892/ijo_00000195
MLA
Ueda, Y., Igishi, T., Hashimoto, K., Suyama, H., Araki, K., Sumikawa, T., Takeda, K., Nakazaki, H., Matsunami, K., Kodani, M., Shigeoka, Y., Matsumoto, S., Shimizu, E."Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: Implication of c-Src and its inhibitor". International Journal of Oncology 34.3 (2009): 689-696.
Chicago
Ueda, Y., Igishi, T., Hashimoto, K., Suyama, H., Araki, K., Sumikawa, T., Takeda, K., Nakazaki, H., Matsunami, K., Kodani, M., Shigeoka, Y., Matsumoto, S., Shimizu, E."Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: Implication of c-Src and its inhibitor". International Journal of Oncology 34, no. 3 (2009): 689-696. https://doi.org/10.3892/ijo_00000195