Inhibitory effects of 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-2) and 2-aminophenoxazine-3-one (Phx-3), which were produced by the reaction of o-aminophenol and its derivatives with bovine hemoglobin, on the proliferation of human malignant melanoma G-361 cells were studied under various conditions. Phx-1 and Phx-3 showed anti-proliferative effects on human malignant melanoma G-361 cells, however Phx-2 did not. Phx-3, which exerted the strongest anti-proliferative effects, inhibited the proliferation of human malignant melanoma G-361 cells during 24 h incubation at concentrations of ≥10 µM. Apoptosis and G1 arrest in the cells, which were detected by DNA laddering on electrophoresis and flow cytometry, respectively, were observed when the melanoma G-361 cells were treated with Phx-3 at 37°C for 24 h. Concomitantly, the increased melanin formation in G-361 cells was indicated by biochemical and morphological detection of melanin within 24 h exposure to Phx-3. The present results suggest that Phx-3 exclusively demonstrates anti-tumor activity against human malignant melanoma G-361 cells by inducing cell cycle accumulation at G1, differentiation and apoptosis.

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