Article
A new synthetic antitumor naphthoquinone induces ROS-mediated apoptosis with activation of the JNK and p38 signaling pathways
Registro en:
ALMEIDA, Patricia D.O. de et al. A new synthetic antitumor naphthoquinone induces ROS-mediated apoptosis with activation of the JNK and p38 signaling pathways. Chemico-Biological Interactions, v. 343, 2021.
0009-2797
10.1016/j.cbi.2021.109444
Autor
Almeida, Patricia D. O. de
Jobim, Gleyce dos Santos Barbosa
Ferreira, Caio César dos Santos
Bernardes, Lucas Rocha
Dias, Rosane Borges
Sales, Caroline Brandi Schlaepfer
Valverde, Ludmila de Faro
Rocha, Clarissa Araújo Gurgel
Soares, Milena Botelho Pereira
Bezerra, Daniel Pereira
Silva, Fernando de Carvalho da
Cardoso, Mariana Filomena do Carmo
Ferreira, Vitor Francisco
Brito, Larissa F.
Sousa, Lirlândia Pires de
Vasconcellos, Marne C. de
Lima, Emerson S.
Resumen
Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira. Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. a Laboratory of Biological Activity, Faculty of Pharmaceutical Sciences, Federal University of Amazonas - UFAM, Manaus, Amazonas, 69077-000, Brazil
b Laboratory of Pathology and Molecular Biology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
c Department of Biomorphology, Institute of Health Sciences, Federal University of Bahia - UFBA, Salvador, Bahia, 40110-902, Brazil
d Laboratory of Tissue Engineering and Immunopharmacology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710,
Brazil
e Laboratory of Carbohydrate and Nucleotide Synthesis, Department of Organic Chemistry, Federal Fluminense University – UFF, Niter´oi, Rio de Janeiro, 24020-141,
Brazil
f Laboratory of Signaling in Inflammation, Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais – UFMG, Belo
Horizonte, Minas Gerais, 31270-901, Brazil CNPq, CAPES and FAPEAM
for their financial support in the form of grants and fellowship awards.
The authors thank to the histotechnology and flow cytometry platforms
of FIOCRUZ-Bahia for the performance of histological techniques and
flow cytometric data acquisition, respectively. The authors also thank to
the Laboratory of Signaling in Inflammation from the Federal University
of Minas Gerais (Belo Horizonte, Minas Gerais, Brazil) by technical
assistance. Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including
antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study,
we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [b]naphtho [2,1-d]
furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against
different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC50 values of
3.06 and 0.98 μM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted
inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin
condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal
DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss
of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that
CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA
transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment
of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein
kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using
melanoma cells in a murine model in vivo, CNFD induced a potent anti-tumor activity. Herein, we describe, for
the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy.