GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC).
Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.
Laboratory of Molecular Oncology, Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585, Japan.
Hisashi
H
Kawazoe
Vladimir N
VN
Bilim
Andrey V
AV
Ugolkov
Kaori
K
Yuuki
Sei
S
Naito
Akira
A
Nagaoka
Tomoyuki
T
Kato
Yoshihiko
Y
Tomita
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001557:Benzenesulfonates / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000008:administration & dosage*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D038362:Glycogen Synthase Kinase 3