Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Marco Varalda; Annamaria Antona; Valentina Bettio; Konkonika Roy; Ajay Vachamaram; Vaibhav Yellenki; Alberto Massarotti; Gianluca Baldanzi; Daniela Capello

doi:10.3389/fonc.2020.562196

Psychotropic Drugs Show Anticancer Activity by Disrupting Mitochondrial and Lysosomal Function

Front Oncol. 2020 Oct 19:10:562196. doi: 10.3389/fonc.2020.562196. eCollection 2020.

Authors

Marco Varalda^{1

2}, Annamaria Antona¹, Valentina Bettio^{1

2}, Konkonika Roy³, Ajay Vachamaram^{1

3}, Vaibhav Yellenki¹, Alberto Massarotti⁴, Gianluca Baldanzi^{1

3}, Daniela Capello^{1

2}

Affiliations

¹ Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, Novara, Italy.
² UPO Biobank, University of Piemonte Orientale, Novara, Italy.
³ Center for Translational Research on Allergic and Autoimmune Diseases (CAAD), University of Piemonte Orientale, Novara, Italy.
⁴ Department Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.

Abstract

Background and Purpose: Drug repositioning is a promising strategy for discovering new therapeutic strategies for cancer therapy. We investigated psychotropic drugs for their antitumor activity because of several epidemiological studies reporting lower cancer incidence in individuals receiving long term drug treatment. Experimental Approach: We investigated 27 psychotropic drugs for their cytotoxic activity in colorectal carcinoma, glioblastoma and breast cancer cell lines. Consistent with the cationic amphiphilic structure of the most cytotoxic compounds, we investigated their effect on mitochondrial and lysosomal compartments. Results: Penfluridol, ebastine, pimozide and fluoxetine, fluspirilene and nefazodone showed significant cytotoxicity, in the low micromolar range, in all cell lines tested. In MCF7 cells these drugs caused mitochondrial membrane depolarization, increased the acidic vesicular compartments and induced phospholipidosis. Both penfluridol and spiperone induced AMPK activation and autophagy. Neither caspase nor autophagy inhibitors rescued cells from death induced by ebastine, fluoxetine, fluspirilene and nefazodone. Treatment with 3-methyladenine partially rescued cell death induced by pimozide and spiperone, whereas enhanced the cytotoxic activity of penfluridol. Conversely, inhibition of lysosomal cathepsins significantly reduced cell death induced by ebastin, penfluridol, pimozide, spiperone and mildly in fluoxetine treated cells. Lastly, Spiperone cytotoxicity was restricted to colorectal cancer and breast cancer and caused apoptotic cell death in MCF7 cells. Conclusions: The cytotoxicity of psychotropic drugs with cationic amphiphilic structures relied on simultaneous mitochondrial and lysosomal disruption and induction of cell death that not necessarily requires apoptosis. Since dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for cancer, particularly those in which the apoptotic machinery is defective, these data further support their clinical development for cancer therapy.

Keywords: autophagy; cancer; cationic amphiphilic drugs (CADs); lysosomotropism; psychotropic drug; repositioning.