IWR-1, a tankyrase inhibitor, attenuates Wnt/β-catenin signaling in cancer stem-like cells and inhibits in vivo the growth of a subcutaneous human osteosarcoma xenograft.

Abstract

Wnt/β-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/β-catenin activation. Here, we investigated whether pharmacological Wnt/β-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma. IWR-1 was specifically cytotoxic for osteosarcoma CSCs. IWR-1 impaired spheres' self-renewal capacity by compromising landmark steps of the canonical Wnt signaling, namely translocation of β-catenin to the nucleus and subsequent TCF/LEF activation and expression of Wnt/β-catenin downstream targets. IWR-1 also hampered the activity and expression of key stemness-related markers. In vitro, IWR-1 induced apoptosis of osteosarcoma spheres and combined with doxorubicin elicited synergistic cytotoxicity, reversing spheres' resistance to this drug. In vivo, IWR-1 co-administration with doxorubicin substantially decreased tumor progression, associated with specific down-regulation of TCF/LEF transcriptional activity, nuclear β-catenin and expression of the putative CSC marker Sox2. We suggest that targeting the Wnt/β-catenin pathway can eliminate CSCs populations in osteosarcoma. Combining conventional chemotherapy with Wnt/β-catenin inhibition may ameliorate therapeutic outcomes, by eradicating the aggressive osteosarcoma CSCs and reducing drug resistance.

• Authors: Sara R Martins-Neves, Daniela I Paiva-Oliveira, Carlos Fontes-Ribeiro, Judith V M G Bovée, Anne-Marie Cleton-Jansen, Célia M F Gomes
• Journal: Cancer letters (Cancer Lett) Vol. 414 Pg. 1-15 (02 01 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 29126913 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• IWR-1 compound
• Imides
• Quinolines
• Doxorubicin
• Tankyrases

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacology)
• Female
• Humans
• Imides (pharmacology)
• Mice, Nude
• Neoplastic Stem Cells (drug effects, metabolism)
• Osteosarcoma (drug therapy, metabolism, pathology)
• Quinolines (pharmacology)
• Tankyrases (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays