Intracellular regulation of evodiamine-induced A375-S2 cell death.
We have reported that in A375-S2 cells, evodiamine isolated from Evodia rutaecarpa induces cell death of human melanoma, A375-S2, through two distinct pathways: apoptosis and necrosis. In the present study, we further demonstrate two different mechanisms by which evodiamine induces apoptosis and necrosis. Although caspase-1 and -10 inhibitors failed to block cell death, pan-caspase inhibitor and caspase-3, -8, and -9 inhibitors had marked inhibitory effects on apoptosis induced by 15 microM evodiamine. Furthermore, evodiamine-induced activation of caspase-3 resulted in the down-regulation of anti-apoptotic Bcl-2 expression and up-regulation of proapoptotic Bax expression. After 24 h incubation with evodiamine, no caspase inhibitor had any influence on cell death, but p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) attenuated cell death; in contrast, extracellular signal-regulated protein kinase (ERK) MAPK inhibitor (PD98059) augmented cell death, as was further confirmed by cotreatment with SB203580 or PD98059 and pan-caspase inhibitor. Moreover, evodiamine increased the phosphorylation of p38 and decreased the expression and phosphorylation of ERK in caspase-independent necrosis. Consequently, evodiamine induced the caspase- and Bax-mediated apoptosis at an early stage, but, initiated MAPKs-dependent necrosis at a later stage.
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
Ying
Y
Zhang
Li-Jun
LJ
Wu
Shin-Ichi
S
Tashiro
Satoshi
S
Onodera
Takashi
T
Ikejima
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D032086:Evodia; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects* / Q000502:physiology; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010936:Plant Extracts; D011799:Quinazolines; C049639:evodiamine; D020169:Caspases