Substituted 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death

Farias,Mirelle Sifroni; Pich,Claus Tröger; Kviecinski,Maicon Roberto; Bucker,Nádia Cristina Falcão; Felipe,Karina Bettega; Da Silva,Fabiana Ourique; Günther,Tânia Mara Fisher; Correia,João Francisco; Ríos,David; Benites,Julio; Valderrama,Jaime A.; Calderon,Pedro Buc; Pedrosa,Rozangela Curi

doi:10.3892/mmr.2014.2160

Substituted 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death

Authors:
- Mirelle Sifroni Farias
- Claus Tröger Pich
- Maicon Roberto Kviecinski
- Nádia Cristina Falcão Bucker
- Karina Bettega Felipe
- Fabiana Ourique Da Silva
- Tânia Mara Fisher Günther
- João Francisco Correia
- David Ríos
- Julio Benites
- Jaime A. Valderrama
- Pedro Buc Calderon
- Rozangela Curi Pedrosa
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Affiliations: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil, Campus Araranguá, University of Santa Catarina, Araranguá 88900-000, Brazil, Faculty of Health Sciences, University of Arturo Prat, Iquique 1100000, Chile
Published online on: April 16, 2014 https://doi.org/10.3892/mmr.2014.2160
Pages: 405-410

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Abstract

Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones (DPB1‑DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor‑bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 µM) and DPB6 was the least cytotoxic one (EC50 56 µM). The 1,4‑naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4‑naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA‑ethidium bromide complexes. Cell death of MCF7 cells induced by 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4‑naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4‑naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%).

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