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In the same setting, combined treatments with ibrutinib plus nutlin-3 led to significantly higher levels of apoptosis compared to the single treatments, counteracting the c-MYC up-regulation. Moreover, the combination induced high p53 levels and a significant dissipation of the mitochondrial membrane potential, together with BAX cleavage in the more active p18 form and phospho-BAD down-regulation, that are key components of the mitochondrial apoptotic pathway, enhancing the apoptosis level. Our findings propose a new therapeutic strategy to overcome the tumor microenvironment protection involved in B-CLL resistance to drugs, with possible clinical implications also for other hematologic and solid tumors for which ibrutinib is considered a therapeutic option.</jats:p>","journal":"Current Oncology","year":2021,"id":670768,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1752226,"name":"Elisabetta Melloni","orcid":"0000-0002-7829-0824","position":1,"is_corresponding":false},{"id":1752227,"name":"Arianna Romani","orcid":"0000-0001-8000-6178","position":2,"is_corresponding":false},{"id":1752228,"name":"Veronica Tisato","orcid":"0000-0001-8448-066X","position":3,"is_corresponding":false},{"id":1109326,"name":"Fabio Casciano","orcid":"0000-0002-6431-3335","position":4,"is_corresponding":false},{"id":1298693,"name":"Gian Matteo Rigolin","orcid":"0000-0002-8370-5190","position":5,"is_corresponding":false},{"id":1752229,"name":"Daniela Milani","orcid":"0000-0002-9540-7801","position":6,"is_corresponding":false},{"id":1752230,"name":"Claudio Celeghini","orcid":null,"position":7,"is_corresponding":false},{"id":1752231,"name":"Giorgio Zauli","orcid":null,"position":8,"is_corresponding":false},{"id":1109329,"name":"Paola Secchiero","orcid":"0000-0003-4101-7987","position":9,"is_corresponding":false},{"id":1752232,"name":"Rebecca Voltan","orcid":"0000-0002-6747-3465","position":10,"is_corresponding":false},{"id":1752225,"name":"Erika Rimondi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors","abstract":"<jats:p>In B-chronic lymphocytic leukemia (B-CLL), the interaction between leukemic cells and the microenvironment promotes tumor cell survival. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is one of the first-in-class molecules for the treatment of B-CLL patients; however, the emerging mechanisms of resistance to ibrutinib call for new therapeutic strategies. The purpose of the current study was to investigate the ability of ibrutinib plus the MDM2-inhibitor nutlin-3 to counteract the tumor microenvironment protective effect. We observed that primary B-CLL cells cultivated in microenvironment mimicking conditions were protected from apoptosis by the up-regulation of c-MYC and of p53. In the same setting, combined treatments with ibrutinib plus nutlin-3 led to significantly higher levels of apoptosis compared to the single treatments, counteracting the c-MYC up-regulation. 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