Repurposing of psychotropic drugs for cancer therapy

Despite improvements in cancer therapy, overall survival for most cancer types has changed a little in the past decades. Drug repositioning represents a promising approach for discovering new therapeutic strategies for cancer therapy. Since several epidemiological studies reported lower cancer incidence in individuals receiving long term psychotropic drugs treatment, in this project we investigated 27 psychotropic drugs for their cytotoxic activity in several cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Penfluridol, ebastine, pimozide, fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested. In MCF7 cells these drugs triggered mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Neither caspase nor autophagy inhibitors rescued cells from death induced by fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine rescued cell death induced by pimozide and spiperone. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly by fluoxetine. Lastly, spiperone caused apoptosis in colorectal and breast. Our unpublished data on the characterization of spiperone activity on adherent and stem-like colorectal cancer cells demonstrated that its cytotoxicity is linked to perturbations of intracellular calcium (Ca2+) homeostasis, which likely result in mitochondrial Ca2+ overload and membrane depolarization, cell cycle block in G1 phase, and apoptosis. Spiperone induced a PLC dependent Ca2+ release from the endoplasmic reticulum (ER) along with ER stress and unfolded protein response activation, resulting in CHOP upregulation. Altogether these data support the clinical development of psychotropic drugs for cancer therapy.