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
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  • Published online on: Sunday, August 1, 2010
  • Pages: 509-517
  • DOI: 10.3892/ijo_00000700

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.
Journal Cover

August 2010
Volume 37 Issue 2

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

2012 Impact Factor: 2.773
Ranked #30/202 Oncology
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APA
Shiota, M., Eto, M., Yokomizo, A., Tada, Y., Takeuchi, A., Itsumi, M., Tatsugami, K., Uchiumi, T., & 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(2), 509-517.
MLA
Shiota, Eto, Yokomizo, Tada, Takeuchi, Itsumi, Tatsugami, Uchiumi, and Seiji Naito. "Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation." International Journal of Oncology International Journal of Oncology 37.2 (2010): 509-517.
Chicago
Shiota, Eto, Yokomizo, Tada, Takeuchi, Itsumi, Tatsugami, Uchiumi, and Seiji Naito. "Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation." International Journal of Oncology International Journal of Oncology 37 no. 2 (2010): 509-517.