抄録
The purpose of this study is to elucidate whether two types of phenoxazine derivatives, 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-amino-phenoxazine-3-one (Phx-3) induce caspase-dependent or independent cell death of human glioblastoma cell lines, A-172 and U-251 MG. Phx-1 and Phx-3 were synthesized by the reactions of bovine hemoglobin with 2-amino-5-methylphenol and o-aminophenol, respectively. These phenoxazines extensively suppressed the proliferation of A-172 and U-251 MG cells (50% inhibition concentration (IC50) of Phx-1: 60 μM in both lines and IC50 of Phx-3: 10 and 3 μM in A-172 and U-251 MG cells, respectively). Phx-1 and Phx-3 increased predominantly the population of both annexin V- and propidium iodide-positive cells in both lines, indicating that these phenoxazines induce cell death at late phase apoptosis/necrosis. Phx-1 and Phx-3 markedly increased the activity of caspase-3/7 in both lines. However, a pan-caspase inhibitor, z-VAD-fmk was not able to attenuate anti-proliferative and apoptotic/necrotic activities of Phx-1 and Phx-3 against both lines, although completely inhibited the activation of caspase-3/7. These results suggest that phenoxazine derivatives, particularly Phx-3 exerts strong anti-proliferative and apoptotic/necrotic effects on human glioblastoma cell lines, A-172 and U-251 MG independent of caspase family signaling cascades. [J Physiol Sci. 2007;57 Suppl:S127]
