Mitochondrial toxicity of the phyotochemicals daphnetoxin and daphnoretin--relevance for possible anti-cancer application.
Daphnetoxin is a daphnane type orthoester diterpene found exclusively in plants of the family Thymelaeaceae while daphnoretin, a bis-coumarin derivative that is the major constituent of the bark of some plants of this family, can also be found in Leguminosae and Rutaceae. These two compounds are recognized to have different biological effects, including a possible anti-cancer activity. The subject of the present research was to compare their mitochondrial toxicity and also investigate a possible selectivity towards tumor cell lines. Wistar rat liver mitochondria and three distinct cell lines were used to investigate compound-induced toxicity. The results indicate that both test compounds are toxic to isolated mitochondrial fractions, especially when used at concentrations higher than 100 microM. However, daphnetoxin presented the highest toxicity including increased proton leak in the inner mitochondrial membrane, increased induction of the mitochondrial permeability transition pore, inhibition of ATP synthase and inhibition of the mitochondrial respiratory chain. Both compounds also inhibited cell proliferation, regardless of the cell line used. Up to the maximal concentration tested in cells, no mitochondrial effects were detected by vital epifluorescence imaging, indicating that inhibition of cell proliferation may also originate from mitochondrial-independent mechanisms. The results warrant careful assessment of toxicity vs. pharmacology benefits of both molecules.
Department of Zoology, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Cátia V
CV
Diogo
Luís
L
Félix
Sérgio
S
Vilela
Ana
A
Burgeiro
Inês A
IA
Barbosa
Maria J M
MJ
Carvalho
Paulo J
PJ
Oliveira
Francisco P
FP
Peixoto
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003374:Coumarins / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D032364:Daphne / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar
D003374:Coumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C035316:daphnoretin; C452759:daphnetoxin; D025261:Mitochondrial Proton-Translocating ATPases