Potentiation of proteasome inhibitor-induced apoptosis in glioma cells by histone deacetylase inhibitors

Abstract

2038 The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Co-exposure of LBH589 (LBH) and botezomib (btzmb) results in a striking induction of apoptosis, at minimally toxic doses of either drug alone, in established U251, U87, and D37 GBM cell lines, as well as in GBM8 (G-8), GBM10 (G-10), GBM12 (G-12), GBM14 (G-14), and GBM56 (G-56) cells, which have been developed from the Mayo xenograft GBM panel and maintained in short-term cultures. Synergism of apoptosis induction was also observed in U251 cells when co-exposing other HDAC inhibitors, including LAQ824 (LAQ) and trichostatin A (TSA), with another proteasome inhibitor MG132, demonstarting a class effect. In U251 cells, btzmb alone or in combination with LBH decreased Raf-1 levels and inactivated Akt and Erk. Either LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly increased JNK activation. In addition, cell death after exposure to LBH589 and bortezomib is associated with cytochrome c release, Bax translocation, as well as caspase and PARP cleavage. Bax translocation may contribute to the synergistic cytotoxicity of the combination of LBH and btzmb in glioma cells since Bax translocation to mitochondria is known to precede cytochrome c release and apoptosis, but other pathways are likely to be involved. This combination regimen warrants further preclinical and possible clinical study for glioma patients. No significant financial relationships to disclose.