Necroptosis is a regulated necrotic cell death that involves receptor-interacting
protein kinases RIPK1 and RIPK3. Here, we report that
edelfosine triggers a rapid and massive cell death in human
glioblastoma cells with characteristics of
necrosis. Only a minor proportion of
edelfosine-treated cells underwent caspase-dependent apoptosis. Autophagy and a rapid influx of extracellular
calcium into the cells had little impact on cell death. Levels of
procaspase-8 were very low in necroptosis-prone
glioma cells compared with the levels in other
cancer cell types that underwent apoptosis upon
edelfosine treatment. The RIPK1-dependent necroptosis inhibitors
necrostatin-1 (Nec-1) and Nec-1s as well as
siRNA-mediated silencing of RIPK3 inhibited
edelfosine-induced necroptosis, resulting in increased caspase-dependent apoptosis in
edelfosine-treated
glioblastoma U118 cells. Inhibition of the RIPK3 substrate MLKL with
necrosulfonamide also increased apoptosis in
edelfosine-treated cells. These data support a major role for RIPK1 and RIPK3 in the induction of necrotic cell death and in the switch from
necrosis to apoptosis following
edelfosine treatment. These results indicate that the
ether lipid edelfosine exerts a rapid necroptotic cell death in apoptosis-reluctant
glioblastoma cells, suggesting that induction of necroptosis could constitute a new approach for
glioblastoma therapy.