Antihistamines induce synergistic cell death when combined with ibrutinib in malignant B cell lines and primary chronic lymphocytic leukemia cells
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Date
2019-08-29
Authors
Chanas-LaRue, Aaron
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Abstract
In chronic lymphocytic leukemia (CLL), malignant monoclonal B cells display aberrant levels of survival related to defects in apoptosis. These cells often develop resistance to therapies targeting susceptible components of the disease, and therefore additional druggable targets are necessary to circumvent this resistance. One such therapeutic target may be the lysosome; CLL cells have previously been shown to be selectively susceptible to cell death induced by lysosomal membrane permeabilization. Furthermore, lysosome targeting drugs have been demonstrated to induce synergistic cell death when combined with tyrosine kinase inhibitors. In this study, H1 antihistamines clemastine, desloratadine, and loratadine have been demonstrated to target lysosomes in malignant B cell lines and primary CLL cells through an oxidative apoptotic mechanism. These drugs were also able to induce synergistic cell death when combined with the tyrosine kinase inhibitor ibrutinib. This synergistic cell death was found to occur through an increase in intracellular reactive oxygen species, mitochondrial dysfunction, and degradation of the anti-apoptotic protein Mcl-1. Taken together, this study proposes to repurpose over-the-counter allergy medications in combination with drugs targeting kinase signalling networks for use as a therapeutic strategy in B cell cancers including CLL.
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Keywords
CLL, Anthistamines, Ibrutinib, Cancer, Therapies, Translational