Abstract
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.
Highlights
Ewing’s sarcoma (ES) is the third most frequent primary bone cancer, and the second most common, after osteosarcoma, in children, adolescents, and young adults
We found that the structurally related inactive edelfosine analog 1-O-octadecyl-rac-glycero-3-phosphocholine (ET-18OH) [25, 38], in which the methoxy group in the sn-2 position of the edelfosine molecule was replaced by an OH group, was unable to trigger apoptosis in both ES cell lines (Figure 1C and 1D), indicating that the proapoptotic activity of edelfosine was highly dependent on its specific chemical structure
We found that edelfosine induced an endoplasmic reticulum (ER) stress response in both CADO-ES1 and RD-ES cell lines, as assessed by a number of ER stress markers (Figure 4B), including caspase-4 activation, CHOP/GADD153 upregulation, eIF2α phosphorylation, and cleavage of Bap31 into the 20-kDa fragment that acts as a linker of proapoptotic signals between ER and mitochondria [44]
Summary
Ewing’s sarcoma (ES) is the third most frequent primary bone cancer, and the second most common, after osteosarcoma, in children, adolescents, and young adults. ES tumors primarily affect children and teenagers, represent almost 3% of pediatric cancers with a peak incidence between the ages of 10 and 15, and are rarely seen in children younger than 5 or adults older than 30 [1,2,3]. ES is a member of Ewing’s family tumors (ESFT) and it is associated in 85-90% of cases with the t(11;22) (q24:q12) chromosomal translocation that generates fusion of the 5’ segment of the EWS gene with the 3’ segment of the ETS family gene FLI-1. The resulting EWS-FLI-1 fusion protein alters transcriptional activity and modulates the expression of a number of downstream target genes relevant to apoptosis, proliferation, and neural differentiation, leading to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways [2, 5].
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