Journal
CANCER LETTERS
Volume 380, Issue 2, Pages 384-392Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.07.006
Keywords
Breast cancer; GSK-3; Chemoresistance; 9-ING-41; Drug development
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Funding
- Robert H. Lurie Comprehensive Cancer Center of North-western University
- Cancer Center Support Grant [2 P30 CA060553-19]
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Glycogen Synthase Kinase-3 beta (GSK-3 beta), a serinejthreonine 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. (C) 2016 Published by Elsevier Ireland Ltd.
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