Abstract: AimTo study the mechanism of evodiamine-induced cell death of A375-S2. MethodsThe changes in cell morphology were observed by invert microscopy and Hoechst 33258 staining. DNA fragmentation was assayed by agarose gel electrophoresis. The effects of evodiamine on apoptosis and cell cycle were studied by flow cytometric analysis. ResultsEvodiamine was shown to markedly inhibit the growth of A375-S2 cells in dose-and time-dependent manners. At the early stage, evodiamine activated caspase cascades, which unexpectedly did not induce typical DNA fragmentation. At later stage, caspase inhibitors failed to block A375-S2 cell death induced by evodiamine. Evodiamine-induced cell death was shown to be not directly associated with cell cycle arrest. ConclusionAt the early stage, evodiamine initiates caspase-dependent and a typical apoptosis pathway in A375-S2 cells, but later it induces cell death through caspase-independent pathway which might be necrosis.