Inhibition of glioma cell growth in vitro and in vivo by a novel proteasome inhibitor

The prognosis of patients with malignant gliomas remains poor. Inhibition of the proteasome of glioma cells may provide a promising therapeutic strategy. Here, we describe the in vitro and in vivo effects of SC68896, a novel agent developed as an inhibitor of the proteasome.

Application of SC68896 to cancer cells of different origin, including gliomas, inhibits their proliferation in vitro. Only nanomolar concentrations are necessary to reduce the enzymatic activity of the proteasome by more than 90%. Exposure of LNT-229 glioma cells to SC68896 results in an accumulation of p21 and p27 proteins, cell cycle arrest, caspase cleavage and induction of apoptosis. Using RNA interference, we demonstrate that the effect of SC68896 on glioma cells is facilitated by a wild-type p53. Administration of SC68896 also efficiently sensitizes glioma cells for TRAIL- or CD95L-induced apoptosis. Using an orthotopic glioma nude mouse model, we observed an increased survival of mice treated either intraperitoneally or intratumorally with SC68896. These data demonstrate that SC68896 has in vitro and in vivo activity against malignant glioma cells and warrants clinical evaluation.