Effects of curcumin and curcumin derivatives on mitochondrial permeability transition pore.
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a natural compound with antiproliferative properties. Recent studies suggest that these properties might be due to the ability of curcumin to induce apoptosis in tumor cells by increasing the permeability of the mitochondrial membrane. In the present study, we confirm these observations and provide a molecular mechanism for the action of curcumin in rat liver mitochondria. Curcumin induced mitochondrial swelling, the collapse of Deltapsi, and the release of cytochrome C, events associated with the opening of the permeability transition pore (PTP). Experiments were performed with chemically substituted curcumin derivatives. Some derivatives were obtained by modification of groups on the terminal aromatic rings, and others were obtained by substitution of the diketone function with the cyclohexanone function. They demonstrated that phenol and methoxy groups were essential to promote PTP opening. Curcumin and curcumin derivatives that open the PTP were able to oxidize thiol groups. In addition, PTP opening was abolished in medium devoid of O2 and decreased in the presence of catalase, ferrozine, o-phenanthroline, mannitol, or N-ethylmaleimide. These data suggest that the mechanism by which curcumin promotes PTP opening involves the reduction of Fe3+ to Fe2+, inducing hydroxyl radical (HO*) production and oxidation of thiol groups in the membrane, leading to pore opening.
Ligeret
Heidi
H
Laboratoire de Pharmacologie, Faculté de Médecine, Créteil, France.
Barthelemy
Sophie
S
Zini
Roland
R
Tillement
Jean-Paul
JP
Labidalle
Serge
S
Morin
Didier
D
D000818:Animals; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005297:Ferrozine / Q000032:analysis / Q000737:chemistry; D007473:Ion Channels / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000378:metabolism
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D005297:Ferrozine; D045304:Cytochromes c; D007501:Iron; D003474:Curcumin