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Cancer Lett. 2016 Oct 1;380(2):384-92. doi: 10.1016/j.canlet.2016.07.006. Epub 2016 Jul 14.

GSK-3 inhibition overcomes chemoresistance in human breast cancer.

Author information

1
Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 2170 Campus Drive, Evanston, IL 60208, USA; Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA.
2
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
3
Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
4
Institute of Genomics and Systems Biology, University of Chicago, 900 East 57th Street, KCBD 10100A, Chicago, IL 60637, USA.
5
Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Galter Suite 3-150, 251 East Huron Street, Chicago, IL 60611, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA.
6
Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA.
7
Department of Medicine, University of Wisconin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Madison, WI 53705, USA.
8
Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 2170 Campus Drive, Evanston, IL 60208, USA; Chemistry of Life Processes Institute, Northwestern University, 2170 Campus Drive, Evanston, IL, 60208, USA; Northwestern Medicine Developmental Therapeutics Institute, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson Pavilion, 233 East Superior Street, Chicago, IL 60611, USA; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Searle Building 8-510, 320 East Superior Street, Chicago, IL 60611, USA. Electronic address: a-mazar@northwestern.edu.

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.

KEYWORDS:

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

PMID:
27424289
PMCID:
PMC5786372
DOI:
10.1016/j.canlet.2016.07.006
[Indexed for MEDLINE]
Free PMC Article

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