title: Sorafenib with doxorubicin augments cytotoxicity to renal cell cancer through PERK inhibition.
abstract: Although cytokine therapy involving interleukin-2 or interferon-alpha has been employed for metastatic renal cell cancer (RCC) treatment, these therapies yielded limited response and benefit. Recently, several molecular-targeted agents have become available, and one newly developed anti-RCC agent, sorafenib (BAY 43-9006), is known to target multiple kinases. In this study, sorafenib was found to inhibit phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha) and induce cell cycle arrest at G2/M phase and increase cell death. One of eIF2alpha kinases, PERK was responsible for eIF2alpha phosphorylation in RCC cells and PERK knockdown induced cell death similar to sorafenib treatment. The efficiency of sorafenib treatment correlated with phosphorylation level of eIF2alpha and nuclear Nrf2 expression level in eight RCC cell lines. Furthermore, sorafenib made Caki-1 and 786-O cells, but not ACHN cells sensitive to oxidative stress exerted by both hydrogen peroxide and doxorubicin. In addition, PERK knockdown sensitized Caki-1 and 786-O cells, but not ACHN cells to oxidative stress. In conclusion, levels of phospho-eIF2alpha and nuclear Nrf2 expression level in RCC might be a predictor of outcome in sorafenib treatment. In addition, PERK inhibition as well as sorafenib plus doxorubicin might be a promising therapeutic approach for RCC characterized by high levels of phosphorylated-eIF2alpha and nuclear Nrf2.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8252, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tada
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Masubuchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kuroiwa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Narihito
authors.initials: N
authors.lastname: Seki
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000008:administration & dosage; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D004317:Doxorubicin / Q000008:administration & dosage; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000201:enzymology*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D034741:RNA, Small Interfering; D000077157:Sorafenib; D019892:eIF-2 Kinase / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001557:Benzenesulfonates; D004317:Doxorubicin; D015852:Eukaryotic Initiation Factor-2; D006861:Hydrogen Peroxide; D051267:NF-E2-Related Factor 2; D009536:Niacinamide; D016877:Oxidants; D010671:Phenylurea Compounds; D011725:Pyridines; D034741:RNA, Small Interfering; D000077157:Sorafenib; D019892:eIF-2 Kinase