Abstract 4345: Proteasome inhibitor, bortezomib, inhibits cell proliferation and induces apoptosis of medulloblastoma cells

Abstract Medulloblastoma is the most common brain tumor in children. Proteasome inhibitors have been reported to inhibit cell proliferation and survival in a variety of tumor cells. Bortezomib (Velcade), an inhibitor of the 26S proteasome, has been approved by FDA to treat multiple myeloma. Here, we investigated effects of bortezomib on human medulloblastoma cells. Bortezomib inhibited cell proliferation and induced apoptosis of Daoy medulloblastoma cells in a time- and dose-dependent manner. Significantly, a relatively low dose of 10 nM bortezomib effectively inhibited the viability of Daoy cells within 48 h. Bortezomib increased the release of cytochrome C to cytosol, resulting in activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Caspase inhibitor (Z-VAD-FMK) could rescue tumor cells from the cytotoxicity of bortezomib on both cell proliferation and survival. Bortezomib increased expression of the pro-apoptotic protein, Bak, and cleavage of the anti-apoptotic protein, Mcl-1. In addition, bortezomib increased the expression of p21Cip1, a negative regulator of cell cycle progression. Bortezomib also induced the accumulation of phosphorylated I[[Unable to Display Character: ĸ]]Bα in Daoy cells, resulting in inhibition of NF[[Unable to Display Character: ĸ]]B signaling. MG-132, another proteasome inhibitor, had similar effects on Daoy cells. Moreover, bortezomib inhibited the growth of human medulloblastoma cells in a mouse xenograft model. Our data suggest that proteasome inhibitors are promising drugs for the treatment of pediatric medulloblastomas. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4345.