PURPOSE: Glioblastomas are among the most lethal neoplasms, with a median survival of <1 year. Modulation of the proteasome function has emerged as a novel approach to cancer pharmacotherapy. Here, we characterized the antitumor properties of SC68896, a novel small molecule proteasome inhibitor. EXPERIMENTAL DESIGN: Different tumor cell lines were tested by crystal violet staining for sensitivity to SC68896, given alone or in combination with death ligands. The molecular mechanisms mediating SC68896-induced cell death and changes in cell cycle progression were assessed by immunoblot and flow cytometry. An orthotopic human glioma xenograft model in nude mice was used to examine the in vivo activity of SC68896. RESULTS: SC68896 inhibits the proliferation of cell lines of different types of cancer, including malignant glioma. Exposure of LNT-229 glioma cells to SC68896 results in a concentration- and time-dependent inhibition of the proteasome, with a consequent accumulation of p21 and p27 proteins, cell cycle arrest, caspase cleavage, and induction of apoptosis. Using RNA interference, we show that the effect of SC68896 on glioma cells is facilitated by wild-type p53. SC68896 sensitizes glioma cells to tumor necrosis factor-related apoptosis-inducing ligand and CD95 ligand and up-regulates the cell surface expression of the tumor necrosis factor-related apoptosis-inducing ligand receptor cell death receptors 4 and 5, which may contribute to this sensitization. Intracerebral glioma-bearing nude mice treated either i.p. or intratumorally with SC68896 experience prolonged survival. CONCLUSIONS: SC68896 is the first proteasome inhibitor that exerts antiglioma activity in vivo. It may represent a novel prototype agent for the treatment of malignant gliomas and warrants clinical evaluation.
PURPOSE:Glioblastomas are among the most lethal neoplasms, with a median survival of <1 year. Modulation of the proteasome function has emerged as a novel approach to cancer pharmacotherapy. Here, we characterized the antitumor properties of SC68896, a novel small molecule proteasome inhibitor. EXPERIMENTAL DESIGN: Different tumor cell lines were tested by crystal violet staining for sensitivity to SC68896, given alone or in combination with death ligands. The molecular mechanisms mediating SC68896-induced cell death and changes in cell cycle progression were assessed by immunoblot and flow cytometry. An orthotopic humanglioma xenograft model in nude mice was used to examine the in vivo activity of SC68896. RESULTS:SC68896 inhibits the proliferation of cell lines of different types of cancer, including malignant glioma. Exposure of LNT-229 glioma cells to SC68896 results in a concentration- and time-dependent inhibition of the proteasome, with a consequent accumulation of p21 and p27 proteins, cell cycle arrest, caspase cleavage, and induction of apoptosis. Using RNA interference, we show that the effect of SC68896 on glioma cells is facilitated by wild-type p53. SC68896 sensitizes glioma cells to tumor necrosis factor-related apoptosis-inducing ligand and CD95 ligand and up-regulates the cell surface expression of the tumor necrosis factor-related apoptosis-inducing ligand receptor cell death receptors 4 and 5, which may contribute to this sensitization. Intracerebral glioma-bearing nude mice treated either i.p. or intratumorally with SC68896 experience prolonged survival. CONCLUSIONS:SC68896 is the first proteasome inhibitor that exerts antiglioma activity in vivo. It may represent a novel prototype agent for the treatment of malignant gliomas and warrants clinical evaluation.
Authors: Merryl R Lobo; Ayaka Kukino; Huong Tran; Matthias C Schabel; Charles S Springer; G Yancey Gillespie; Marjorie R Grafe; Randall L Woltjer; Martin M Pike Journal: PLoS One Date: 2015-12-08 Impact factor: 3.240