Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung cancer cells.
The mechanisms of the antitumor reactions of 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) to human lung adenocarcinoma A549 cells were investigated. A549 cells that received 1.25 microg/ml FNQ3 (IC(50) at 0.35 microg/ml) developed intensive mitochondrial H(2)O(2) production at 1 h. Selective structural mitochondrial swelling, alteration of mitochondrial membrane potential, and cytochrome c and caspase-9 release from the mitochondria occurred 18-24 h later. alpha-Tocopherol inhibited the alteration of both mitochondrial permeability and the leakage of procaspase-9. The caspase-9 was then activated in the cytosol. The expression of Bcl-2 oncoprotein was suppressed by FNQ3, and resulted in apoptosis. The higher dose of 5 microg/ml induced necrosis via severe mitochondrial breakage. These results showed that FNQ3 targets the mitochondria of A549 cells to produce a reactive oxygen species resulting in apoptosis and necrosis.
Simamura
Eriko
E
Department of Anatomy, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. simamura@kanazawa-med.ac.jp
Hirai
Kei-Ichi
K
Shimada
Hiroki
H
Pan
Jiehong
J
Koyama
Junko
J
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009285:Naphthoquinones / Q000494:pharmacology*; D009336:Necrosis; D010539:Permeability / Q000187:drug effects; D014407:Tumor Cells, Cultured; D024502:alpha-Tocopherol / Q000494:pharmacology
C106805:2-methylnaphtho(2,3-b)furan-4,9-dione; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D003574:Cytochrome c Group; D009285:Naphthoquinones; D006861:Hydrogen Peroxide; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D024502:alpha-Tocopherol