The anti-cancer agent nemorosone is a new potent protonophoric mitochondrial uncoupler.
Nemorosone, a natural-occurring polycyclic polyprenylated acylphloroglucinol, has received increasing attention due to its strong in vitro anti-cancer action. Here, we have demonstrated the toxic effect of nemorosone (1-25 μM) on HepG2 cells by means of the MTT assay, as well as early mitochondrial membrane potential dissipation and ATP depletion in this cancer cell line. In mitochondria isolated from rat liver, nemorosone (50-500 nM) displayed a protonophoric uncoupling activity, showing potency comparable to the classic protonophore, carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Nemorosone enhanced the succinate-supported state 4 respiration rate, dissipated mitochondrial membrane potential, released Ca(2+) from Ca(2+)-loaded mitochondria, decreased Ca(2+) uptake and depleted ATP. The protonophoric property of nemorosone was attested by the induction of mitochondrial swelling in hyposmotic K(+)-acetate medium in the presence of valinomycin. In addition, uncoupling concentrations of nemorosone in the presence of Ca(2+) plus ruthenium red induced the mitochondrial permeability transition process. Therefore, nemorosone is a new potent protonophoric mitochondrial uncoupler and this property is potentially involved in its toxicity on cancer cells.
Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, La Lisa, Ciudad Habana, Cuba. gilbertopardo@infomed.sld.cu
Gilberto L
GL
Pardo-Andreu
Yanier
Y
Nuñez-Figueredo
Valeria G
VG
Tudella
Osmany
O
Cuesta-Rubio
Fernando P
FP
Rodrigues
Cezar R
CR
Pestana
Sérgio A
SA
Uyemura
Andréia M
AM
Leopoldino
Luciane C
LC
Alberici
Carlos
C
Curti
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D001577:Benzophenones; C437463:nemorosone; D000255:Adenosine Triphosphate; D002118:Calcium