Final Report Summary - LYSOSOME (Lysosomes as targets for cancer therapy)
The main achievement of this interdisciplinary project is the identification, characterization and validation of commonly used cationic amphiphilic drugs (e.g. ebastine and loratadine antihistamines) as potent anti-cancer drugs. Regarding their mechanism of action, we have identified an early lysosomal calcium release and subsequent calcium-dependent synthesis of cyclic AMP as a signaling route mediating CAD-induced lysosomal membrane permeabilization and cell death. Prompted by the significant CAD-induced changes in the lysosomal lipidome, we have identified cholesterol and lysoglycerophopholipid as lipids that protect and sensitize lysosomes to CAD-induced leakage. These mechanistic insights open several possibilities to further sensitize cancer cells to CADs, e.g. with cAMP-inducing asthma drugs or cholesterol-lowering statins. Based on the data obtained, clinical trials to test the efficacy of ebastine and loratadine in cancer treatment are already in progress.