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 μg/ml FNQ3 (IC50 at 0.35 μg/ml) developed intensive mitochondrial H2O2 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. α-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 μg/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.