Sensitivity of doxorubicin-resistant cells to sorafenib: possible role for inhibition of eukaryotic initiation factor-2alpha phosphorylation.
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-2alpha (eIF2alpha), induce cell cycle arrest at G2 phase and increase cellular apoptosis in doxorubicin-resistant human urothelial cell lines. An eIF2alpha kinase, PERK was responsible for eIF2alpha 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 eIF2alpha.
Shiota
Masaki
M
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8252, Japan.
Eto
Masatoshi
M
Yokomizo
Akira
A
Tada
Yasuhiro
Y
Takeuchi
Ario
A
Itsumi
Momoe
M
Tatsugami
Katsunori
K
Uchiumi
Takeshi
T
Naito
Seiji
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001557:Benzenesulfonates; D004317:Doxorubicin; D015852:Eukaryotic Initiation Factor-2; D006861:Hydrogen Peroxide; D009536:Niacinamide; D010671:Phenylurea Compounds; D011725:Pyridines; D000077157:Sorafenib; D019892:eIF-2 Kinase