Proteasome inhibition by bortezomib does not translate into efficacy on two malignant glioma xenografts

Bortezomib and other proteasome inhibitors have demonstrated an interesting antitumor activity against glioma cell lines. The present study aimed to evaluate the cytotoxic potential of bortezomib in vivo on two human malignant glioma xenografts using doses relevant to clinical practice. The TCG3 and U87 malignant glioma xenografts were heterotopically implanted onto nude mice. Bortezomib effects were evaluated using the three different doses of 0.25, 0.45 and 0.90 mg/kg. Proteasome chymotrypsin-like activity was measured by a fluorimetric method. Analysis of the cell cycle distribution was performed after propidium iodide staining. The apoptotic rate and proliferative index were determined by an immunohistochemical detection of cleaved caspase-3 and Ki-67, respectively. Our data showed that bortezomib induced a dose-dependent inhibition of proteasome chymotrypsin-like activity in the two glioma models. Maximal inhibition was achieved 24 h after drug injection and was approximately 30% of basal proteasome activity. However, this effect did not induce any increase in the apoptotic rate and did not modify cell cycle distribution. At the maximal dose tested (0.90 mg/kg), bortezomib did not show any growth delay as compared to untreated tumors, in either of the xenograft models. In conclusion, our study is the first to demonstrate that bortezomib, at a clinically relevant dose, did not have any effect on the apoptosis and proliferation of malignant gliomas in vivo. These results contrast with the promising preclinical data obtained in vitro with this drug and emphasize the importance of performing preclinical studies on animal models, in conditions close to clinical settings.