4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one induces mitochondrial dysfunction and apoptosis upon its intracellular oxidation.
We investigated the mechanism of cell death induced by a furoquinolinone derivative, namely, 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), in the dark. Mitochondrial depolarization was found to be a causative event in HOFQ-induced apoptosis that was blunted either by replacing the 4-hydroxymethyl group with a methyl one, or by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase (ADH). In vitro enzymatic assay demonstrated that HOFQ is a substrate of ADH. In isolated mitochondria HOFQ was without effect, whereas in the presence of ADH and NAD(+) it caused the opening of the permeability transition pore, indicating that HOFQ-oxidized products affect mitochondrial function directly. Finally, an analogue bearing the formyl group at the C-4 position mimicked all the effects exerted by HOFQ. In conclusion, these results suggest that the direct action on mitochondria of HOFQ-oxidized products are responsible for their cytotoxicity, which might be exacerbated, but hardly determined, by photodynamic action and/or binding to DNA.
Chilin
Adriana
A
Department of Pharmaceutical Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Dodoni
Giuliano
G
Frezza
Christian
C
Guiotto
Adriano
A
Barbieri
Vera
V
Di Lisa
Fabio
F
Canton
Marcella
M
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001671:Biochemistry / Q000379:methods; D002843:Chromatin / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003624:Darkness; D005663:Furans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008967:Molecular Biology / Q000379:methods; D010084:Oxidation-Reduction; D010539:Permeability; D015363:Quinolones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C450158:4-hydroxymethyl-1,6,8-trimethylfuro(2,3-h)quinolin-2(1H)-one; D000590:Amino Acid Chloromethyl Ketones; D002843:Chromatin; D015853:Cysteine Proteinase Inhibitors; D005663:Furans; D015363:Quinolones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000426:Alcohol Dehydrogenase