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Characterization of the antitumoral properties of excited and ground state phenothiazines by focusing their action on mitochondria, lysosomes and biological membranes


The thiazine derivatives with substitutions at the 2- and 10-positions of thiazinic nucleus are widely used in the treatment of schizophrenia. These compounds also present pro-apoptotic and photochemical properties. In this work we will characterize the anticancer potential of three phenothiazine derivatives, thioridazine (TR), fluphenazine (FP) and trifluoperazine (TFP) in the ground and excited states based on their actions on mitochondria, lysosomes and biological membranes. Our preliminary results showed that phenothiazines in the ground state are able to alter the permeability of mitochondria and lysosomes and these actions probably are related to the induction of apoptosis in tumor cells. Moreover, we recently demonstrated that phenothiazines are able to induce a photo-oxidative damage in isolated mitochondria due to the generation of a phenothiazine cation radical. The complete molecular characterization of the effects of phenothiazines proposed in this project will constitute important contribution for the understanding of their biological effects and will provide the basis to a potential utilization of phenothiazines as anticancer agents. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CRUZ, THIAGO S.; FARIA, PRISCILA A.; SANTANA, DEBORA P.; FERREIRA, JULIANA C.; OLIVEIRA, VITOR; NASCIMENTO, OTACIRO R.; CERCHIARO, GISELLE; CURTI, CARLOS; NANTES, ISELI L.; RODRIGUES, TIAGO. On the mechanisms of phenothiazine-induced mitochondrial permeability transition: Thiol oxidation, strict Ca2+ dependence, and cyt c release. Biochemical Pharmacology, v. 80, n. 8, p. 1284-1295, . (06/00995-9, 08/01724-4)
DO CARMO, ALINE LAGOEIRO; BETTANIN, FERNANDA; ALMEIDA, MICHELL ALMEIDA; PANTALEAO, SIMONE QUEIROZ; RODRIGUES, TIAGO; HOMEM-DE-MELLO, PAULA; HONORIO, KATHIA MARIA. Competition Between Phenothiazines and BH3 Peptide for the Binding Site of the Antiapoptotic BCL-2 Protein. FRONTIERS IN CHEMISTRY, v. 8, . (06/00995-9, 16/07367-5, 17/23416-9, 16/24524-7, 17/10118-0)
SANTANA, DEBORA P.; FARIA, PRISCILA A.; PAREDES-GAMERO, EDGAR J.; CAIRES, ANTONIO C. F.; NANTES, ISELI L.; RODRIGUES, TIAGO. Palladacycles catalyse the oxidation of critical thiols of the mitochondrial membrane proteins and lead to mitochondrial permeabilization and cytochrome c release associated with apoptosis. Biochemical Journal, v. 417, n. 1, p. 247-256, . (06/00995-9)

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