Antihistamines are synergistic with Bruton's tyrosine kinase inhibiter ibrutinib mediated by lysosome disruption in chronic lymphocytic leukemia (CLL) cells

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.