A second life for MAO inhibitors: from CNS diseases to cancer

Monoamine oxidase (MAO) subtypes A and B are the enzymes responsible for the oxidative deamination of amine neurotransmitters. Selective MAO A and B inhibitors are currently used as second-line drugs for the treatment of depression and Parkinson’s disease, respectively. MAO inhibitors with additional, multitarget activities are widely studied for their potential in the treatment of neurodegenerative diseases, although to date none still enter clinics. Interestingly, recent studies report on the effectiveness of isoform-selective MAO inhibitors in contrasting chemoresistance and invasiveness of several types of cancers [1], thus suggesting a potential of MAO inhibition in chemotherapy. Particularly, MAO A selective inhibitors proved to be able to overcome the chemoresistance of highly recurrent prostate cancer (PC) [2], and indeed the MAO A irreversible inhibitor phenelzine is currently under clinical investigation in non-metastatic recurrent PC [3]. Other evidences suggest an antiproliferative effect in other types of cancer, possibly related to the drop of oxidative stress induced by MAO inhibition [4]. Based on our long-standing experience in the discovery of potent and selective MAO A/B inhibitors [5], we are currently investigating a possible antiproliferative activity of coumarin-based MAO A selective inhibitors in MCF-7 and MDA-MB231 breast cancer cells. The first outcome of this study will be presented, either in terms of intrinsic cytostatic activity or in light of possible synergistic effects in co-administration with known anticancer drugs and in other antiproliferative features, like the inhibition of tumor cell migration, a known MAO-mediated tumorigenic event.