Academic Journal
Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
| العنوان: | Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma |
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| المؤلفون: | Recasens-Zorzo, Clara, Cardesa-Salzmann, Teresa, Petazzi, Paolo, Ros-Blanco, Laia, Esteve-Arenys, Anna, Clot, Guillem, Guerrero-Hernández, Martina, RodrÃguez, Vanina, Soldini, Davide, Valera, Alexandra, Moros, Alexandra, Climent, Fina, Gonzalez-Barca, Eva, Mercadal, Santiago, Arenillas, Leonor, Calvo, Xavier, Mate Sanz, Jose LuÃs, Gutiérrez-GarcÃa, Gonzalo, Casanova Rigat, Isolda, Mangues, Ramon, Sanjuan-Pla, Alejandra, Bueno, Clara, Menéndez Bujan, Pablo, MartÃnez, Antonio, Colomer, Dolors, Estrada-Tejedor, Roger, Teixidó, Jordi, Campo, Elias, López-Guillermo, A., Borrell, José Ignacio, Colomo, Luis, Pérez-Galán, Patricia, Roué, Gaël, Universitat Autònoma de Barcelona |
| سنة النشر: | 2019 |
| المجموعة: | Universitat Autònoma de Barcelona: Dipòsit Digital de Documents de la UAB |
| مصطلحات موضوعية: | Acetamides, Animals, Azepines, Biopsy, Cell Line, Tumor, Cemokine CXCL12, Female, Humans, Lymphoma, Large B-Cell, Diffuse, MAP Kinase Signaling System, Male, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Proto-Oncogene Proteins c-akt, Receptors, CXCR4, Xenograft Model Antitumor Assays |
| الوصف: | Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| ردمك: | 978-85-06-40082-1 85-06-40082-1 |
| تدمد: | 15928721 |
| Relation: | Haematologica; Vol. 104 Núm. 4 (31 2019), p. 778-788; https://ddd.uab.cat/record/236800; urn:10.3324/haematol.2017.180505; urn:oai:ddd.uab.cat:236800; urn:scopus_id:85064008215; urn:articleid:15928721v104n4p778; urn:pmid:29954928; urn:pmcid:PMC6442946; urn:oai:pubmedcentral.nih.gov:6442946 |
| الاتاحة: | https://ddd.uab.cat/record/236800 |
| Rights: | open access ; Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. ; https://creativecommons.org/licenses/by-nc/4.0/ |
| رقم الانضمام: | edsbas.AC6CAD4D |
| قاعدة البيانات: | BASE |
Full Text Finder | ردمك: | 9788506400821 8506400821 |
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| تدمد: | 15928721 |