Ewing's sarcoma (ES) is the second most common
bone cancer in children and young people.
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is the prototype of a family of synthetic antitumor compounds, collectively known as alkylphospholipid analogs (APLs). We have found that APLs ranked
edelfosine>
perifosine>
erucylphosphocholine>
miltefosine for their capacity to promote apoptosis in ES cells.
Edelfosine accumulated in the endoplasmic reticulum (ER) and triggered an ER stress response that eventually led to caspase-dependent apoptosis in ES cells. This apoptotic response involved mitochondrial-mediated processes, with
cytochrome c release,
caspase-9 activation and generation of
reactive oxygen species.
Edelfosine-induced apoptosis was also dependent on sustained c-Jun NH2-terminal
kinase activation.
Oral administration of
edelfosine showed a potent in vivo antitumor activity in an ES xenograft animal model. Histochemical staining gave evidence for ER stress response and apoptosis in the ES
tumors isolated from
edelfosine-treated mice.
Edelfosine showed a preferential action on ES
tumor cells as compared to non-transformed osteoblasts, and appeared to be well suited for combination
therapy regimens. These results demonstrate in vitro and in vivo antitumor activity of
edelfosine against ES cells that is mediated by
caspase activation and ER stress, and provide the proof of concept for a putative
edelfosine- and ER stress-mediated approach forES treatment.