| 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 |
Affiliations:
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8252, Japan
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Doi: 10.3892/ijo_00000700 |
Pages: 509-517 |
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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