Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia
| العنوان: | Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia |
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| المؤلفون: | Pietro Delfino, Paul Takam Kamga, Adriana Cassaro, Annalisa Adamo, Giada Dal Collo, Mauro Krampera, Carmine Carbone, Massimiliano Bonifacio, Alice Bonato, Riccardo Bazzoni, Ilaria Tanasi |
| المساهمون: | 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., Immunology |
| المصدر: | Cancers, Vol 12, Iss 2696, p 2696 (2020) Cancers Cancers, MDPI, 2020, 12 (9), pp.1-16. ⟨10.3390/cancers12092696⟩ Cancers, 12(9):2696. Multidisciplinary Digital Publishing Institute (MDPI) Volume 12 Issue 9 |
| بيانات النشر: | MDPI AG, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c1383615cc64e49ca94880602ea61c2 https://www.mdpi.com/2072-6694/12/9/2696 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2c1383615cc64e49ca94880602ea61c2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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