Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment

Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug ( CAD) library for cytotoxicity against NSCLC cells and identified several CAD antihistaminesas inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamineuse on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non- CAD antihistaminesand adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizoleshowed a similar significant association with reduced mortality as loratadineamong patients with any non-localized cancer, and ebastineuse showed a similar tendency. The association between CAD antihistamineuse and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizoleand ebastinesensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistaminesmay improve the efficacy of cancer chemotherapy.