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

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

Author Faria, Priscila A. de Google Scholar
Bettanin, Fernanda Google Scholar
Cunha, Rodrigo L. O. R. Google Scholar
Paredes-Gamero, Edgar J. Autor UNIFESP Google Scholar
Homem-de-Mello, Paula Google Scholar
Nantes, Iseli L. Google Scholar
Rodrigues, Tiago Google Scholar
Institution Universidade Federal do ABC (UFABC)
Universidade Federal de São Paulo (UNIFESP)
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.
Keywords HTC cells
Cytotoxicity
Mitochondrial permeability transition
Phenothiazine
Cell death
Structure-activity
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 2012/12247-8
FAPESP: 2010/19790-3
CNPq: 476824/2010-9
CNPq: 310669/2013-8
Date 2015-04-01
Published in Toxicology. Clare: Elsevier B.V., v. 330, p. 44-54, 2015.
ISSN 0300-483X (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 44-54
Origin http://dx.doi.org/10.1016/j.tox.2015.02.004
Access rights Closed access
Type Article
Web of Science ID WOS:000351803400005
URI http://repositorio.unifesp.br/handle/11600/38957

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