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ToxSci Advance Access originally published online on February 13, 2006
Toxicological Sciences 2006 91(1):173-183; doi:10.1093/toxsci/kfj127
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene

Aleksandra Isakovic*, Zoran Markovic{dagger}, Biljana Todorovic-Markovic{dagger}, Nadezda Nikolic{dagger}, Sanja Vranjes-Djuric{dagger}, Marija Mirkovic{dagger}, Miroslav Dramicanin{dagger}, Ljubica Harhaji{ddagger}, Nevena Raicevic{ddagger}, Zoran Nikolic§ and Vladimir Trajkovic,1

* Institute of Biochemistry, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia and Montenegro; {dagger} Vinca Institute of Nuclear Sciences, 11000 Belgrade, Serbia and Montenegro; {ddagger} Institute for Biological Research, 11000 Belgrade, Serbia and Montenegro; § Faculty of Physics, University of Belgrade, 11000 Belgrade, Serbia and Montenegro; and Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia and Montenegro

Received November 18, 2005; accepted February 1, 2006

The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C60) and water-soluble polyhydroxylated fullerene [C60(OH)n] were investigated. Crystal violet assay for cell viability demonstrated that nano-C60 was at least three orders of magnitude more toxic than C60(OH)n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V–fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C60 caused rapid (observable after few hours), reactive oxygen species (ROS)–associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C60(OH)n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C60 toxicity, but not C60(OH)n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C60(OH)n-induced apoptosis, but not nano-C60–mediated necrosis. Finally, C60(OH)n antagonized, while nano-C60 synergized with, the cytotoxic action of oxidative stress–inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.

Key Words: cytotoxicity; fullerene; C60; reactive oxygen species; apoptosis; necrosis.


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