The role of phenothiazine derivatives in autophagy regulation: A systematic review

In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)‐dependent or mTOR‐independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs. In this review, we analyzed 35 papers about the impact of phenothiazines on autophagy in vitro. Phenothiazines are antipsychotic drugs which may cause dysregulation of neuronal autophagy. We have found that all of the analyzed drugs can modulate autophagy (the final effect depends on the used concentration and the cell line), and autophagy stimulation by phenothiazines may be either mTOR‐dependent or mTOR‐independent. A further investigation is required to understand the biological actions and to increase the therapeutic potential of phenothiazine derivatives.