GSK-3 Inhibition in Vitro and in Vivo Enhances Antitumor Effect of Sorafenib in Renal Cell Carcinoma (RCC)

Biochem Biophys Res Commun. 2012 Jul 6;423(3):490-5. doi: 10.1016/j.bbrc.2012.05.147. Epub 2012 Jun 5.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols
  • Benzenesulfonates / therapeutic use*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / enzymology
  • Cell Proliferation / drug effects
  • Glycogen Synthase Kinase 3 / administration & dosage*
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / enzymology
  • Mice
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines / therapeutic use*
  • Sorafenib
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Niacinamide
  • Sorafenib
  • Glycogen Synthase Kinase 3