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4299273 
Journal Article 
Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species 
Di Rosso, ME; Barreiro Arcos, ML; Elingold, I; Sterle, H; Baptista Ferreira, S; Ferreira, VF; Galleano, M; Cremaschi, G; Dubin, M 
2013 
1 
Toxicology In Vitro
ISSN: 0887-2333
EISSN: 1879-3177 
27 
7 
2094-2104 
English 
23933437 
WOS:000326361000009 
Novel β-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1μM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n-acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway. 
; Acetylcysteine/pharmacology; Animals; Antineoplastic Agents/antagonists & inhibitors; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Benzopyrans/antagonists & inhibitors; Benzopyrans/pharmacology; Benzoquinones/metabolism; Cell Line; Tumor; Cell Nucleus Shape/drug effects; Cell Proliferation/drug effects; Cell Survival/drug effects; Chromatin Assembly and Disassembly/drug effects; Free Radical Scavengers/pharmacology; Glutathione/antagonists & inhibitors; Glutathione/metabolism; Kinetics; Lymphoma; T-Cell/drug therapy; Lymphoma; T-Cell/metabolism; Lymphoma; T-Cell/pathology; Membrane Potential; Mitochondrial/drug effects; Mice; Naphthoquinones/antagonists & inhibitors; Naphthoquinones/pharmacology; Reactive Oxygen Species/antagonists & inhibitors; Reactive Oxygen Species/metabolism; Trypanocidal Agents/antagonists & inhibitors; Trypanocidal Agents/pharmacology; Up-Regulation/drug effects; Index Medicus/