2. Academic Validation
  3. 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

  • Cancer Lett. 2018 Feb 1:414:1-15. doi: 10.1016/j.canlet.2017.11.004.
Sara R Martins-Neves 1,  Daniela I Paiva-Oliveira 2,  Carlos Fontes-Ribeiro 2,  Judith V M G Bovée 3,  Anne-Marie Cleton-Jansen 3,  Célia M F Gomes 4
Affiliations

Affiliations

  • 1 Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; CIMAGO, University of Coimbra, Coimbra, Portugal; Department of Pathology, Leiden University Medical Center, P.O.Box 9600, L1-Q, 2300 RC, Leiden, The Netherlands.
  • 2 Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
  • 3 Department of Pathology, Leiden University Medical Center, P.O.Box 9600, L1-Q, 2300 RC, Leiden, The Netherlands.
  • 4 Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; CIMAGO, University of Coimbra, Coimbra, Portugal. Electronic address: cgomes@fmed.uc.pt.
PMID: 29126913 DOI: 10.1016/j.canlet.2017.11.004
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.

Keywords

Apoptosis; Cancer stem-like cells; Doxorubicin; IWR-1; Osteosarcoma; Wnt/β-catenin signaling.

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