Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: A structure-activity investigation

Full text
Author(s):
de Faria, Priscila A. [1] ; Bettanin, Fernanda [1] ; Cunha, Rodrigo L. O. R. [1] ; Paredes-Gamero, Edgar J. [2] ; Homem-de-Mello, Paula [1] ; Nantes, Iseli L. [1] ; Rodrigues, Tiago [1]
Total Authors: 7
Affiliation:
[1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil
[2] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Toxicology; v. 330, p. 44-54, APR 1 2015.
Web of Science Citations: 16
Abstract

Phenothiazine derivatives are neuroleptic drugs used in the treatment of schizophrenia and anxiety. Several side effects are described for these drugs, including hepatotoxicity, which may be related to their cytotoxic activity. Working with isolated rat liver mitochondria, we previously showed that phenothiazine derivatives induced the mitochondrial permeability transition associated with cytochrome c release. Since the mitochondrial permeabilization process plays a central role in cell death, the aim of this work was to evaluate the effects of five phenothiazine derivatives (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, and triflupromazine) on the viability of hepatoma tissue culture (HTC) cells to establish the structural requirements for cytotoxicity. All phenothiazine derivatives decreased the viability of the HTC cells in a concentration-dependent manner and exhibited different cytotoxic potencies. The EC50 values ranged from 45 to 125 mu M, with the piperidinic derivative thioridazine displaying the most cytotoxicity, followed by the piperazinic and aliphatic derivatives. The addition of the phenothiazine derivatives to cell suspensions resulted in significant morphological changes and plasma membrane permeabilization. Octanol/water partition studies revealed that these drugs partitioned preferentially to the apolar phase, even at low pH values (>= 4.5). Also, structural and electronic properties were calculated employing density functional theory. Interestingly, the phenothiazine derivatives promoted an immediate dissipation of the mitochondrial transmembrane potential in HTC cells, and the EC50 values were closely correlated with those obtained in cell viability assays, as well as the EC50 for swelling in isolated mitochondria. These results significantly contribute to improving our understanding of the specific structural requirements of the phenothiazine derivatives to induce cell death and suggest the involvement of the mitochondrial permeability transition in phenothiazine-induced cytotoxicity in HTC cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved. (AU)

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: 10/19790-3 - Theoretical study of porphyrins, phthalocyanines and CHLORINES with enphasis for use in photodynamic therapy
Grantee:Fernanda Bettanin
Support Opportunities: Scholarships in Brazil - Doctorate