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A new synthetic antitumor naphthoquinone induces ROS-mediated apoptosis with activation of the JNK and p38 signaling pathways.

Authors
  • de Almeida, Patricia D O1
  • Dos Santos Barbosa Jobim, Gleyce1
  • Dos Santos Ferreira, Caio César1
  • Rocha Bernardes, Lucas1
  • Dias, Rosane B2
  • Schlaepfer Sales, Caroline B3
  • Valverde, Ludmila de F2
  • Rocha, Clarissa A G2
  • Soares, Milena B P4
  • Bezerra, Daniel P4
  • de Carvalho da Silva, Fernando5
  • Cardoso, Mariana Filomena do Carmo5
  • Ferreira, Vitor Francisco5
  • Brito, Larissa F6
  • Pires de Sousa, Lirlândia6
  • de Vasconcellos, Marne C1
  • Lima, Emerson S7
  • 1 Laboratory of Biological Activity, Faculty of Pharmaceutical Sciences, Federal University of Amazonas - UFAM, Manaus, Amazonas, 69077-000, Brazil. , (Brazil)
  • 2 Laboratory of Pathology and Molecular Biology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. , (Brazil)
  • 3 Laboratory of Pathology and Molecular Biology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil; Department of Biomorphology, Institute of Health Sciences, Federal University of Bahia - UFBA, Salvador, Bahia, 40110-902, Brazil. , (Brazil)
  • 4 Laboratory of Tissue Engineering and Immunopharmacology, Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. , (Brazil)
  • 5 Laboratory of Carbohydrate and Nucleotide Synthesis, Department of Organic Chemistry, Federal Fluminense University - UFF, Niterói, Rio de Janeiro, 24020-141, Brazil. , (Brazil)
  • 6 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. , (Brazil)
  • 7 Laboratory of Biological Activity, Faculty of Pharmaceutical Sciences, Federal University of Amazonas - UFAM, Manaus, Amazonas, 69077-000, Brazil. Electronic address: [email protected] , (Brazil)
Type
Published Article
Journal
Chemico-biological interactions
Publication Date
Apr 30, 2021
Volume
343
Pages
109444–109444
Identifiers
DOI: 10.1016/j.cbi.2021.109444
PMID: 33939975
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2021 Elsevier B.V. All rights reserved.

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