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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Biochemical Pharmacology; v. 222, p. 9-pg., 2024-02-24.

Resumo

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)

• Processo FAPESP: 21/14650-3 - Trocador sódio-cálcio (NCX): papel na homeostase de cálcio, metabolismo energético e proliferação tumoral
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/12247-8 - Novas aplicações de fenotiazinas e paladaciclos: utilização de sistemas nanoestruturados para o estudo dos mecanismos de morte em células tumorais
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/00995-9 - Caracterização das propriedades antitumorais de fenotiazinas nos estados fundamental e excitado com base em sua ação sobre mitocôndrias, lisossomos e membranas biológicas
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/07367-5 - Investigação dos Mecanismos de Indução de Morte Celular por Fenotiazinas em Células Tumorais: Modulação da Expressão Gênica e Papel das Proteínas da Família BCL-2 e Estresse do Retículo Endoplasmático
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular