Targeting autophagy by antipsychotic phenothiazines: potential drug repurposing for cancer therapy

Author(s)

Lopes, Rayssa M. ; Souza, Ana Carolina S. ; Otreba, Michal ; Rzepecka-Stojko, Anna ; Tersariol, Ivarne L. S. ; Rodrigues, Tiago

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 222, p. 9-pg., 2024-02-24.

Abstract

Cancer is recognized as the major cause of death worldwide and the most challenging public health issues. Tumor cells exhibit molecular adaptations and metabolic reprograming to sustain their high proliferative rate and autophagy plays a pivotal role to supply the high demand for metabolic substrates and for recycling cellular components, which has attracted the attention of the researchers. The modulation of the autophagic process sensitizes tumor cells to chemotherapy -induced cell death and reverts drug resistance. In this regard, many in vitro and in vivo studies having shown the anticancer activity of phenothiazine (PTZ) derivatives due to their potent cytotoxicity in tumor cells. Interestingly, PTZ have been used as antiemetics in antitumor chemotherapyinduced vomiting, maybe exerting a combined antitumor effect. Among the mechanisms of cytotoxicity, the modulation of autophagy by these drugs has been highlighted. Therefore, the use of PTZ derivatives can be considered as a repurposing strategy in antitumor chemotherapy. Here, we provided an overview of the effects of antipsychotic PTZ on autophagy in tumor cells, evidencing the molecular targets and discussing the underlying mechanisms. The modulation of autophagy by PTZ in tumor cells have been consistently related to their cytotoxic action. These effects depend on the derivative, their concentration, and also the type of cancer. Most data have shown the impairment of autophagic flux by PTZ, probably due to the blockade of lysosomeautophagosome fusion, but some studies have also suggested the induction of autophagy. These data highlight the therapeutic potential of targeting autophagy by PTZ in cancer chemotherapy. (AU)

• FAPESP's process: 21/14650-3 - Sodium-calcium exchangers and cancer: role in calcium homeostasis, energy metabolism and tumor proliferation
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/12247-8 - New applications of phenothiazines and Palladacycles: nanostructured systems to the mechanistic study of death in tumor cells
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 06/00995-9 - Characterization of the antitumoral properties of excited and ground state phenothiazines by focusing their action on mitochondria, lysosomes and biological membranes
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07367-5 - Investigation of Phenothiazine-Induced Cell Death Mechanisms In Tumor Cells: Changes in Gene Expression, Role of Bcl-2 Family Proteins, and ER Stress
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants