Antihistamines are synergistic with Bruton's tyrosine kinase inhibiter ibrutinib mediated by lysosome disruption in chronic lymphocytic leukemia (CLL) cells
| Autor: | James B. Johnston, Elizabeth S. Henson, Aaron Chanas-Larue, Spencer B. Gibson, Gloria E. Villalpando-Rodriguez |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
medicine.drug_class Chronic lymphocytic leukemia medicine.medical_treatment Histamine Antagonists Apoptosis Tyrosine-kinase inhibitor Targeted therapy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines hemic and lymphatic diseases medicine Agammaglobulinaemia Tyrosine Kinase Tumor Cells Cultured Bruton's tyrosine kinase Humans biology business.industry Adenine Drug Synergism Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell Pyrimidines Oncology chemistry 030220 oncology & carcinogenesis Ibrutinib Clemastine biology.protein Cancer research Pyrazoles business Lysosomes Tyrosine kinase 030215 immunology medicine.drug Signal Transduction |
| Zdroj: | Leukemia research. 96 |
| ISSN: | 1873-5835 |
| Popis: | Lysosomes in chronic lymphocytic leukemia (CLL) cells have previously been identified as a promising target for therapeutic intervention in combination with targeted therapies. Recent studies have shown that antihistamines can induce lysosomal membrane permeabilization (LMP) in a variety of cell lines. Furthermore, our previous data indicates that lysosomotropic agents can cause synergistic cell death in vitro when combined with some tyrosine kinase inhibitors (TKI). In the current study, we have shown that three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death via LMP in CLL cells, as compared to normal lymphocytes. We treated primary CLL cells with antihistamines and found clemastine was the most effective at inducing LMP and cell death. More importantly, the antihistamines induced synergistic cytotoxicity when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy. Moreover, the synergy between clemastine and ibrutinib was associated with the induction of reactive oxygen species (ROS), loss of mitochondrial membrane potential and decreased Mcl-1 expression leading to apoptosis. This study proposes a potential novel treatment strategy for CLL, repurposing FDA-approved allergy medications in combination with the targeted therapy ibrutinib to enhance drug efficacy. |
| Databáze: | OpenAIRE |
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