Antidepressants synergize with chemotherapy against cancer stem cells

1], the antidepressant drug desmethylclomipramine has shown an interesting synergistic effect with cisplatin, gemcitabine or placlitax on lung cancer stem cells. The fact that antidepressant drugs potentiate chemotherapy in poorly responding cancer is of major relevance, and opens up potential innovative therapeutic effects. But what are the underlying molecular mechanisms for this therapy? Can this be transferred to other poorly responding cancers? We originally identified the HECT containing ITCH as the ubiquitin E3 ligase responsible for the degradation of p63 and p73, and, based on that, we performed an high throughput (HTS) screening using an ELISA-based HTS with purified recombinant proteins and GST-auto-ubiquitylation as readout for ITCH activity [2]. The automated HTS on a 22,000 compound library was robust, according to an average recorded Z' of 0.7 (range 0.5-0.7), and resulted in the identification of 46 compounds showing <50% residual activity, 20 of which were confirmed at single point, and 6 of these showed a dose-dependent inhibition of ITCH. The most active validated inhibitors were the antidepressant drugs clomipramine, norclomipramine and their active metabolite desmethylclomipramine [2]. Interestingly, the validation and analysis of the results revealed clomipramine as a regulator of autophagy [2-3]. This was an intriguing observation as clomipramine has been used for over 40 years for the treatment of patients with psychiatric disorders, with a long-standing record of tolerance and safety. Antidepressants are known to act on the serotonin uptake, so the inhibition of an E3 ligase would suggest that either there is an alternative mode of action, or that an ITCH-related E3 ligase is involved in the process, for example as a regulator of the receptor or of the intracellular recycling pathway. Still, the regulation of autophagy opens interesting opportunities for cancer therapy based on the evidence that autophagy inhibitors potentiate the effect of chemotherapy. Indeed several clinical trials are under way in phase I-II using chloroquine to potentiate chemotherapy (e.g. NCT01649947). In vitro, clomipramine does potentiate the effect of chemotherapeutic agents on different Editorial bladder, breast, prostate cancer cell lines [2]. However, to be more effective, this effect should be tested on cancer stem cells. And indeed, the work of Bongiorno-Borbone et al. [1] revealed that clomipramide compounds have a significant effect on the growth properties of lung cancer stem cells isolated from non-small-cell lung cancers' surgical specimens. Desmethylclomipramine, by interfering with the autophagic flux and blocking the degradation of the autophagic cargo, decreases the stemness potential …