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.
Highlights
Non-small cell lung cancer (NSCLC) is one of the most common cancers and the leading cause of cancer death worldwide (Siegel et al, 2015)
Data presented above suggest that addition of clinically relevant doses of well-tolerated cationic amphiphilic drug (CAD) antihistamines to the standard cancer chemotherapy regiment improves cancer prognosis
The observed positive effect of CAD antihistamines is likely to be related to their CAD structure rather than their antihistamine effect or the disease they have been prescribed for
Summary
Non-small cell lung cancer (NSCLC) is one of the most common cancers and the leading cause of cancer death worldwide (Siegel et al, 2015). As is the case for most advanced cancers, acquired apoptosis and therapy resistance pose, major challenges for the treatment of NSCLC (Chang, 2011). Besides being tumor-promoting, these lysosomal changes associate with reduced lysosomal membrane stability (Fehrenbacher et al, 2008, Fehrenbacher et al, 2004) This frailty of cancer cell lysosomes can be targeted by several cationic amphiphilic drugs (CADs) that accumulate in the acidic lysosomes and induce lysosomal damage preferentially in cancer cells (Ostenfeld et al, 2008, Petersen et al, 2013, Sukhai et al, 2013, Jahchan et al, 2013, Shchors et al, 2015)
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