GSK-3 inhibition overcomes chemoresistance in human breast cancer

Cancer Lett. 2016 Oct 1;380(2):384-392. doi: 10.1016/j.canlet.2016.07.006. Epub 2016 Jul 14.


Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine protein kinase, is an emerging therapeutic target in the treatment of human breast cancer. In this study, we demonstrate that the pharmacological inhibition of GSK-3 by two novel small molecule GSK-3 inhibitors, 9-ING-41 and 9-ING-87, reduced the viability of breast cancer cells but had little effect on non-tumorigenic cell growth. Moreover, treatment with 9-ING-41 enhanced the antitumor effect of irinotecan (CPT-11) against breast cancer cells in vitro. We next established two patient-derived xenograft tumor models (BC-1 and BC-2) from metastatic pleural effusions obtained from patients with progressive, chemorefractory breast cancer and demonstrated that 9-ING-41 also potentiated the effect of the chemotherapeutic drug CPT-11 in vivo, leading to regression of established BC-1 and BC-2 tumors in mice. Our results suggest that the inhibition of GSK-3 is a promising therapeutic approach to overcome chemoresistance in human breast cancer, and identify the GSK-3 inhibitor 9-ING-41 as a candidate targeted agent for metastatic breast cancer therapy.

Keywords: 9-ING-41; Breast cancer; Chemoresistance; Drug development; GSK-3.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Indoles / pharmacology*
  • Irinotecan
  • Maleimides / pharmacology*
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • Time Factors
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-f)indol-7-yl)-pyrrole-2,5-dione
  • Antineoplastic Agents, Phytogenic
  • Indoles
  • Maleimides
  • Protein Kinase Inhibitors
  • Irinotecan
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Camptothecin