Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors
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...
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doaj-5f530f4e178242669dbc74f8c127f8fc2021-09-20T10:10:04ZengMDPI AGCurrent Oncology1198-00521718-77292021-07-01282232439245110.3390/curroncol28040223Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological InhibitorsErika Rimondi0Elisabetta Melloni1Arianna Romani2Veronica Tisato3Fabio Casciano4Gian Matteo Rigolin5Daniela Milani6Claudio Celeghini7Giorgio Zauli8Paola Secchiero9Rebecca Voltan10Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalySection of Hematology, Department of Medical Sciences, University of Ferrara, 44122 Ferrara, ItalyDepartment of Translational Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyDepartment of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, ItalyIn 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. 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.https://www.mdpi.com/1718-7729/28/4/223leukemiaMDM2 inhibitorBTK inhibitorp53apoptosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Erika Rimondi Elisabetta Melloni Arianna Romani Veronica Tisato Fabio Casciano Gian Matteo Rigolin Daniela Milani Claudio Celeghini Giorgio Zauli Paola Secchiero Rebecca Voltan |
spellingShingle |
Erika Rimondi Elisabetta Melloni Arianna Romani Veronica Tisato Fabio Casciano Gian Matteo Rigolin Daniela Milani Claudio Celeghini Giorgio Zauli Paola Secchiero Rebecca Voltan Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors Current Oncology leukemia MDM2 inhibitor BTK inhibitor p53 apoptosis |
author_facet |
Erika Rimondi Elisabetta Melloni Arianna Romani Veronica Tisato Fabio Casciano Gian Matteo Rigolin Daniela Milani Claudio Celeghini Giorgio Zauli Paola Secchiero Rebecca Voltan |
author_sort |
Erika Rimondi |
title |
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors |
title_short |
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors |
title_full |
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors |
title_fullStr |
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors |
title_full_unstemmed |
Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors |
title_sort |
overcoming of microenvironment protection on primary chronic lymphocytic leukemia cells after treatment with btk and mdm2 pharmacological inhibitors |
publisher |
MDPI AG |
series |
Current Oncology |
issn |
1198-0052 1718-7729 |
publishDate |
2021-07-01 |
description |
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. 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. |
topic |
leukemia MDM2 inhibitor BTK inhibitor p53 apoptosis |
url |
https://www.mdpi.com/1718-7729/28/4/223 |
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