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%).

Albendazole as a promising molecule for tumor control

“…Then, half of each group was euthanized for the evaluation of the ascitic fluid. Tumor growth was determined using the following equation [20] : Inhibition of tumor growth (%)=100- [(variation in waist circumference of the treated group×100)/variation in waist circumference of the control group]. Mice (n=6) from each group were kept alive to determine survival time [21] , [22] .…”

Ehrlich ascites tumor-bearing mice treated with aqueous ethanol plant extract from <i>Euphorbia tirucalli</i> showed signs of systemic toxicity

“…Cells were counted by a TC10 counter (BioRad, USA). Inhibition of tumor growth (ITG) was calculated with basis on abdominal circumference change (AC) using Equation 1 [18]:…”

Two novel 1,4‑naphthoquinone derivatives induce human gastric cancer cell apoptosis and cell cycle arrest by regulating reactive oxygen species‑mediated MAPK/Akt/STAT3 signaling pathways

“…1,4-Naphthoquinone exhibits a variety of biological activities, and its superior anticancer activity has attracted widespread attention (14,15). Many 1,4-naphthoquinone derivatives (plumbagin, mitomycin and shikonin) have been demonstrated to strongly inhibit the proliferation and induce apoptosis in cancer cells, but most of the derivatives also cause adverse side effects in normal cells (16). Previous studies have demonstrated that different substituent structures enable naphthoquinone derivatives to have different biological activities (17,18).…”