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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2017 Sep 16; Vol. 491 (2), pp. 463-468. Date of Electronic Publication: 2017 Jul 14. - Publication Year :
- 2017
-
Abstract
- Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG <subscript>0</subscript> cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Antigens, CD
Antineoplastic Agents chemistry
Cadherins genetics
Cadherins metabolism
Caspase 3 genetics
Caspase 3 metabolism
Cell Cycle drug effects
Cell Line, Tumor
Drug Synergism
Epithelial-Mesenchymal Transition drug effects
Gene Expression Regulation
Humans
Isoxazoles chemistry
Mesenchymal Stem Cells metabolism
Mesenchymal Stem Cells pathology
Niacinamide chemistry
Niacinamide pharmacology
Poly(ADP-ribose) Polymerases genetics
Poly(ADP-ribose) Polymerases metabolism
Sarcoma, Ewing genetics
Sarcoma, Ewing metabolism
Sarcoma, Ewing pathology
Signal Transduction
Small Molecule Libraries chemistry
Vimentin genetics
Vimentin metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Isoxazoles pharmacology
Mesenchymal Stem Cells drug effects
Niacinamide analogs & derivatives
Small Molecule Libraries pharmacology
TNF-Related Apoptosis-Inducing Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 491
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 28716733
- Full Text :
- https://doi.org/10.1016/j.bbrc.2017.07.050