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WNT/β-catenin and Hedgehog signaling pathways as therapeutic targets in B-cell neoplasms
C. Ferreira1,2,, , J. Jorge2,4, R. Alves2,3, A.C. Gonçalves2,3,4, A.B. Sarmento-Ribeiro2,3,4,5
1 Department of Chemistry, Biochemical, University of Aveiro, Portugal
2 Laboratory of Oncobiology and Hematology (LOH), University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine, University of Coimbra, Portugal
3 Center for Neuroscience and Cell Biology, IBILI (CNC.IBILI), University of Coimbra, Portugal
4 CIMAGO - Center of Investigation on Environment Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Portugal
5 Clinical Hematology Service, University Hospital of Coimbra, Portugal

Aim: The goal of this study was to evaluate the therapeutic potential of WNT/β-catenin and Hedgehog inhibitors, IWR-1 and GDC-0449 respectively, alone and in combination, in B-cell neoplasms.

Introduction: B-cell neoplasms include, among others, the B-cell lymphomas and plasma cell disorders, such as multiple myeloma (MM), a malignant neoplasm originated by proliferation of monoclonal plasma cells; and diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma. Inappropriate activation of conserved embryonic signaling pathways, such as WNT/β-catenin and Hedgehog has been implicated in B-cell neoplasms. Hence, these pathways may constitute new potential candidate targets for MM and DLBCL therapy.

Methods: For this propose, H929 (MM) and FARAGE (DLBCL) cell lines, were cultured in absence and presence of different concentrations of IWR and GDC. Metabolic activity was evaluated using resazurin assay and cell death by optical microscopy (May-Grunwald staining) and flow cytometry (FC) (Annexin V/7-AAD staining). Cell cycle analysis was evaluated by FC, using a PI/RNAse solution. Proteins related to apoptosis and some molecules related to WNT and HH signaling pathways were tested by FC. The expression levels of AXIN and SMO genes were analyzed by RT-PCR.

Results: Preliminary results showed that IWR-1 and GDC-0449 reduced metabolic activity in a time,- dose- and cell line dependent manner, when administrated alone or in combination. The IC50 of IWR-1 and GDC-0449 in H929 cells was 40μM and 70μM, respectively, and 75μM and 57μM for FARAGE cell line, after 24h of treatment. These compounds induce cell death mainly by apoptosis and showed an arrest in cell cycle at G0/G1. Complementary studies are still ongoing.

Conclusion: In conclusion, results suggest that IWR-1 and GDC-0449 are potential new targeted therapies that could be efficient in MM and DLBCL treatment.

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