Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
| Autor: | Recasens-Zorzo, Clara, Cardesa-Salzmann, Teresa, Petazzi, Paolo, Ros-Blanco, Laia, Esteve-Arenys, Anna, Clot, Guillem, Guerrero-Hernández, Martina, Rodríguez, Vanina, Soldini, Davide, Valera, Alexandra, Moros, Alexandra, Climent, Fina, Gonzalez-Barca, Eva, Mercadal, Santiago, Arenillas, Leonor, Calvo, Xavier, Mate Sanz, Jose Luís, Gutiérrez-García, Gonzalo, Casanova Rigat, Isolda, Mangues, Ramon, Sanjuan-Pla, Alejandra, Bueno, Clara, Menéndez Bujan, Pablo, Martínez, Antonio, Colomer, Dolors, Estrada Tejedor, Roger, Teixidó, Jordi, Campo, Elias, López-Guillermo, A., Borrell, José I, Colomo, Luis, Pérez-Galán, Patricia, Roué, Gaël, Universitat Autònoma de Barcelona |
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| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Receptors CXCR4 Limfomes MAP Kinase Signaling System medicine.medical_treatment Non-Hodgkin Lymphoma Biopsy Cèl·lules B Limfomes -- Tractament Article 03 medical and health sciences Chemokine receptor Mice 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Acetamides Medicine Animals Humans Receptor Mitogen-Activated Protein Kinase 1 B cells Mitogen-Activated Protein Kinase 3 business.industry Hematology Azepines Cemokine CXCL12 medicine.disease Xenograft Model Antitumor Assays Chemokine CXCL12 3. Good health Bromodomain Lymphoma Cytokine Tumor progression Cancer research Female Lymphomas Lymphoma Large B-Cell Diffuse business Diffuse large B-cell lymphoma Proto-Oncogene Proteins c-akt 030215 immunology |
| Zdroj: | HAEMATOLOGICA r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname Haematologica r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau Recercat. Dipósit de la Recerca de Catalunya Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Dipòsit Digital de la UB Universidad de Barcelona r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol |
| ISSN: | 0390-6078 |
| Popis: | Constitutive activation of the chemokine receptor CXCR4 has be en 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. |
| Databáze: | OpenAIRE |
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