Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo.
Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
INSERM U421, Faculté de Médecine 2 étage, Creteil, France.
Nathalie
N
Laurent
Sophie
S
de Boüard
Jean-Sébastien
JS
Guillamo
Christo
C
Christov
Roland
R
Zini
Hélène
H
Jouault
Patrice
P
Andre
Vincent
V
Lotteau
Marc
M
Peschanski
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005909:Glioblastoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; D019438:Ritonavir