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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Eric J Rellinger1, Chandrasekhar Padmanabhan2, Jingbo Qiao1

  • 1Section of Surgical Sciences, Department of Surgery, United States; Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.

Biochemical and Biophysical Research Communications
|July 19, 2017
PubMed

Insights

The small molecule ML327 partially reverses mesenchymal-to-epithelial transition in Ewing sarcoma cells, inducing apoptosis. It also sensitizes these cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Ewing sarcoma is a rare pediatric cancer originating from mesenchymal cells, often with poor prognosis in metastatic cases.
  • Epithelial-to-mesenchymal transition (EMT) is linked to cancer progression and apoptosis resistance in carcinomas.
  • ML327 is a novel molecule known to reverse EMT features in other cancer types.

Purpose of the Study:

  • To investigate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells.
  • To determine if ML327 induces growth arrest and sensitizes Ewing sarcoma to TNF-related apoptosis-inducing ligand (TRAIL).

Main Methods:

  • Treatment of multiple Ewing sarcoma cell lines (SK-N-MC, TC71, ES-5838) with ML327.
  • Analysis of protein expression changes (E-cadherin, vimentin), apoptosis markers (PARP, Caspase 3 cleavage), and cell cycle distribution.
  • In vitro combination treatment with ML327 and TRAIL.

Main Results:

  • ML327 induced changes in protein expression, increasing E-cadherin and decreasing vimentin, indicating a partial mesenchymal-to-epithelial transition (MET).
  • Apoptosis was observed, evidenced by PARP and Caspase 3 cleavage and an increased subG0 cell population.
  • Combination treatment with TRAIL showed additive effects on apoptosis induction.

Conclusions:

  • ML327 demonstrates potential in reversing mesenchymal characteristics and inducing apoptosis in Ewing sarcoma cells.
  • ML327 shows promise as a therapeutic agent for Ewing sarcoma, both as a single agent and in combination with TRAIL.
  • Further in vivo studies are warranted to explore the therapeutic efficacy of ML327 in mesenchymal tumors.
Keywords:
ApoptosisEpithelial-to-mesenchymal transitionEwing sarcomaIsoxazoleML327TRAIL

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