Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation

  • Authors:
    • Masaki Shiota
    • Masatoshi Eto
    • Akira Yokomizo
    • Yasuhiro Tada
    • Ario Takeuchi
    • Momoe Itsumi
    • Katsunori Tatsugami
    • Takeshi Uchiumi
    • Seiji Naito
  • View Affiliations

  • Published online on: August 1, 2010     https://doi.org/10.3892/ijo_00000700
  • Pages: 509-517
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Abstract

Patients with advanced cancer including breast cancer, hepatocellular cancer and urothelial cancer frequently receive a chemotherapy regimen containing doxorubicin. However, doxorubicin-resistance is a major obstacle for cancer chemotherapy. Recently, several molecular-targeted agents have become available. Sorafenib (BAY 43-9006) is known to target multiple kinases and has demonstrated activity in renal cell and hepatocellular cancer. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2α (eIF2α), induce cell cycle arrest at G2 phase and increase cellular apoptosis in doxorubicin-resistant human urothelial cell lines. An eIF2α kinase, PERK was responsible for eIF2α phosphorylation and PERK knockdown induced cellular apoptosis similar to sorafenib treatment in doxorubicin-resistant cancer cells. Furthermore, sorafenib sensitized doxorubicin-resistant cancer cells, but not their parental cells to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized doxorubicin-resistant cancer cells to oxidative stress. In conclusion, PERK inhibition using sorafenib with or without doxorubicin might be a promising therapeutic approach for doxorubicin-resistant cancers retaining high phosphorylation levels of eIF2α.

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August 2010
Volume 37 Issue 2

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

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Spandidos Publications style
Shiota M, Eto M, Yokomizo A, Tada Y, Takeuchi A, Itsumi M, Tatsugami K, Uchiumi T and Naito S: Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation. Int J Oncol 37: 509-517, 2010
APA
Shiota, M., Eto, M., Yokomizo, A., Tada, Y., Takeuchi, A., Itsumi, M. ... Naito, S. (2010). Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation. International Journal of Oncology, 37, 509-517. https://doi.org/10.3892/ijo_00000700
MLA
Shiota, M., Eto, M., Yokomizo, A., Tada, Y., Takeuchi, A., Itsumi, M., Tatsugami, K., Uchiumi, T., Naito, S."Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation". International Journal of Oncology 37.2 (2010): 509-517.
Chicago
Shiota, M., Eto, M., Yokomizo, A., Tada, Y., Takeuchi, A., Itsumi, M., Tatsugami, K., Uchiumi, T., Naito, S."Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation". International Journal of Oncology 37, no. 2 (2010): 509-517. https://doi.org/10.3892/ijo_00000700