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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

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

Sara R Martins-Neves, Daniela I Paiva-Oliveira, Carlos Fontes-Ribeiro, Judith V M G Bovée, Anne-Marie Cleton-Jansen, Célia M F Gomes

Cancer Lett. 2018 Feb 1;414:1-15.

PMID: 29126913

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4243595	IWR-1			Price

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