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 language | English |
|---|---|
| Pages (from-to) | 509-517 |
| Number of pages | 9 |
| Journal | International journal of oncology |
| Volume | 37 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 1 2010 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
Sensitivity of doxorubicin-resistant cells to sorafenib : Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation. / Shiota, Masaki; Eto, Masatoshi; Yokomizo, Akira; Tada, Yasuhiro; Takeuchi, Ario; Itsumi, Momoe; Tatsugami, Katsunori; Uchiumi, Takeshi; Naito, Seiji.
In: International journal of oncology, Vol. 37, No. 2, 01.08.2010, p. 509-517.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sensitivity of doxorubicin-resistant cells to sorafenib
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
Y1 - 2010/8/1
N2 - 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.
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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UR - http://www.scopus.com/inward/citedby.url?scp=77954149972&partnerID=8YFLogxK
U2 - 10.3892/ijo-0000700
DO - 10.3892/ijo-0000700
M3 - Article
C2 - 20596679
AN - SCOPUS:77954149972
VL - 37
SP - 509
EP - 517
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 2
ER -