Multiple mechanisms underlying the anticancer action of nanocrystalline fullerene.
Using the rat glioma cell line C6 and the human glioma cell line U251, we demonstrate the multiple mechanisms underlying the in vitro anticancer effects of the C(60) fullerene water suspension (nano-C(60) or nC(60)) produced by solvent exchange method. Nano-C(60) in a dose-dependent manner reduced the tumor cell numbers after 24 h of incubation. The observed antiglioma action of nC(60) at high concentration (1 microg/ml) was due to a reactive oxygen species-mediated necrotic cell damage that was partly dependent on oxidative stress-induced activation of extracellular signal-regulated kinase (ERK). On the other hand, low-dose nC(60) (0.25 microg/ml) did not induce either necrotic or apoptotic cell death, but caused oxidative stress/ERK-independent cell cycle block in G(2)/M phase and subsequent inhibition of tumor cell proliferation. Treatment with either high-dose or low-dose nC(60) caused the appearance of acidified intracytoplasmic vesicles indicative of autophagy, but only the antiglioma effect of low-dose nC(60) was significantly attenuated by inhibiting autophagy with bafilomycin A1. Importantly, primary rat astrocytes were less sensitive than their transformed counterparts to a cytostatic action of low-dose nC(60). These data provide grounds for further development of nC(60) as an anticancer agent.
Harhaji
Ljubica
L
Institute for Biological Research, Belgrade, Serbia and Montenegro.
Isakovic
Aleksandra
A
Raicevic
Nevena
N
Markovic
Zoran
Z
Todorovic-Markovic
Biljana
B
Nikolic
Nadezda
N
Vranjes-Djuric
Sanja
S
Markovic
Ivanka
I
Trajkovic
Vladimir
V
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D037741:Fullerenes / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053758:Nanoparticles; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D037741:Fullerenes; D005904:Glial Fibrillary Acidic Protein; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases