1. Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia
- Author
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Pietro Delfino, Paul Takam Kamga, Adriana Cassaro, Annalisa Adamo, Giada Dal Collo, Mauro Krampera, Carmine Carbone, Massimiliano Bonifacio, Alice Bonato, Riccardo Bazzoni, Ilaria Tanasi, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Stem Cell Research Laboratory, University of Verona (UNIVR), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Niguarda Hospital [Milan, Italy], University of Milan, University and Hospital Trust of Verona, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Funding: This work was supported by: (i) Progetti di Rilevante Interesse Nazionale (PRIN) Italia, Bando 2017, (ii) Fondazione CARIVERONA Italia, Bando 2012., and Immunology
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0301 basic medicine ,Cancer Research ,Stromal cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:RC254-282 ,Article ,drug target ,03 medical and health sciences ,Wnt ,0302 clinical medicine ,AML ,In vivo ,medicine ,Niclosamide ,business.industry ,Wnt signaling pathway ,Myeloid leukemia ,LRP6 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,microenvironment ,In vitro ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,business ,medicine.drug - Abstract
Wnt/&beta, catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied&mdash, in vitro and in vivo&mdash, the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of &beta, catenin, Ser675-phospho-&beta, catenin and GSK-3&alpha, (total and Ser 9) were found in AML cells from intermediate or poor risk patients, nevertheless, patients presenting high activity of Wnt/&beta, catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/&beta, catenin inhibition that may represent a potential new therapeutics strategy in AML.
- Published
- 2020
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