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

Masaki Shiota, Masatoshi Eto, Akira Yokomizo, Yasuhiro Tada, Ario Takeuchi, Momoe Itsumi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito

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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.

Original languageEnglish
Pages (from-to)509-517
Number of pages9
JournalInternational journal of oncology
Volume37
Issue number2
DOIs
Publication statusPublished - Aug 1 2010

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Eukaryotic Initiation Factor-2
Doxorubicin
Phosphorylation
Neoplasms
Liver Neoplasms
Oxidative Stress
Apoptosis
Breast Neoplasms
sorafenib
Drug Therapy
G2 Phase
Cell Cycle Checkpoints
Renal Cell Carcinoma
Hydrogen Peroxide
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation",
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.",
author = "Masaki Shiota and Masatoshi Eto and Akira Yokomizo and Yasuhiro Tada and Ario Takeuchi and Momoe Itsumi and Katsunori Tatsugami and Takeshi Uchiumi and Seiji Naito",
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T2 - Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation

AU - Shiota, Masaki

AU - Eto, Masatoshi

AU - Yokomizo, Akira

AU - Tada, Yasuhiro

AU - Takeuchi, Ario

AU - Itsumi, Momoe

AU - Tatsugami, Katsunori

AU - Uchiumi, Takeshi

AU - Naito, Seiji

PY - 2010/8/1

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AB - 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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