title: Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment.
abstract: 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 antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use 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 antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use 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, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy.
authors.affiliation: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ellegaard
authors.affiliation: Statistics, Bioinformatics & Registry, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Dehlendorff
authors.affiliation: Department of Veterinary Disease Biology, Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, DK-2100 Copenhagen, Denmark.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Vind
authors.affiliation: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Atul
authors.initials: A
authors.lastname: Anand
authors.affiliation: Statistics, Bioinformatics & Registry, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Luise
authors.initials: L
authors.lastname: Cederkvist
authors.affiliation: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Nikolaj H T
authors.initials: NHT
authors.lastname: Petersen
authors.affiliation: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Nylandsted
authors.affiliation: Department of Veterinary Disease Biology, Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, DK-2100 Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.affiliation: Department of Oncology, Copenhagen University Hospital Herlev, DK-2730 Herlev, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Mellemgaard
authors.affiliation: Department of Oncology, Copenhagen University Hospital Rigshospitalet, DK-2200 DK-2730 Copenhagen, Denmark.
authors.forename: Kell
authors.initials: K
authors.lastname: Østerlind
authors.affiliation: Statistics, Bioinformatics & Registry, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Friis
authors.affiliation: Cell Death & Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark. Electronic address: mj@cancer.dk.
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D000072283:A549 Cells; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D016589:Astemizole / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003718:Denmark; D058492:Drug Repositioning; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D017336:Loratadine / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008247:Lysosomes / Q000378:metabolism; D016016:Proportional Hazards Models; D012042:Registries; D015996:Survival Rate
chemical_list: D002412:Cations; D006633:Histamine Antagonists; D017336:Loratadine; D016589:Astemizole