title: 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.
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%).
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Mirelle Sifroni
authors.initials: MS
authors.lastname: Farias
authors.affiliation: Campus Araranguá, University of Santa Catarina, Araranguá 88900-000, Brazil.
authors.forename: Claus Tröger
authors.initials: CT
authors.lastname: Pich
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Maicon Roberto
authors.initials: MR
authors.lastname: Kviecinski
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Nádia Cristina Falcão
authors.initials: NC
authors.lastname: Bucker
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Karina Bettega
authors.initials: KB
authors.lastname: Felipe
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Fabiana Ourique
authors.initials: FO
authors.lastname: Da Silva
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Tânia Mara Fisher
authors.initials: TM
authors.lastname: Günther
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: João Francisco
authors.initials: JF
authors.lastname: Correia
authors.affiliation: Faculty of Health Sciences, University of Arturo Prat, Iquique 1100000, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Ríos
authors.affiliation: Faculty of Health Sciences, University of Arturo Prat, Iquique 1100000, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Benites
authors.affiliation: Faculty of Health Sciences, University of Arturo Prat, Iquique 1100000, Chile.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Valderrama
authors.affiliation: Faculty of Health Sciences, University of Arturo Prat, Iquique 1100000, Chile.
authors.forename: Pedro Buc
authors.initials: PB
authors.lastname: Calderon
authors.affiliation: Laboratory of Experimental Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil.
authors.forename: Rozangela Curi
authors.initials: RC
authors.lastname: Pedrosa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C523365:2-phenylamino-1,4-naphthoquinone; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D004247:DNA