GSK-3 inhibition overcomes chemoresistance in human breast cancer

Andrey Ugolkov, Irina Gaisina, Jin San Zhang, Daniel D. Billadeau, Kevin White, Alan Kozikowski, Sarika Jain, Massimo Cristofanilli, Francis Giles, Thomas O'Halloran, Vincent L. Cryns, Andrew P. Mazar*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)384-392
Number of pages9
JournalCancer Letters
Volume380
Issue number2
DOIs
StatePublished - Oct 1 2016

Keywords

  • 9-ING-41
  • Breast cancer
  • Chemoresistance
  • Drug development
  • GSK-3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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