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Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors,

Ying Huang1, Xiang Yang2, Tianrui Xu2

  • 1Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.

International Journal of Oncology
|May 24, 2016
PubMed

Insights

This study shows that combining TRAIL with inhibitors of c-FLIP and IAPs (ART therapy) effectively overcomes cancer cell resistance to TRAIL-induced apoptosis. This novel approach demonstrates significant promise for developing new cancer treatments without harming normal cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy due to its specific cancer cell killing ability.
  • TRAIL-based therapies face challenges due to widespread cancer cell resistance.
  • Targeting apoptosis pathways is crucial for effective cancer treatment.

Purpose of the Study:

  • To investigate a novel combination therapy to overcome TRAIL resistance in cancer cells.
  • To evaluate the efficacy of ART (TRAIL, AT406, rocaglamide) in inducing apoptosis in TRAIL-resistant cancer cell lines.
  • To assess the safety of ART therapy on normal cells.

Main Methods:

  • Utilized siRNA or rocaglamide to downregulate c-FLIP expression.
  • Employed AT406, a pan-inhibitor of Inhibitor of Apoptosis Proteins (IAPs).
  • Tested the combination therapy (ART) on multiple solid cancer cell lines and glioma cell lines.

Main Results:

  • The ART combination significantly enhanced TRAIL-induced apoptosis in most tested solid cancer cell lines.
  • ART therapy demonstrated effectiveness in 15 out of 18 TRAIL-resistant cancer cell lines.
  • Two glioma cell lines showed resistance to ART due to low procaspase-8 levels.
  • Normal cells were not harmed by the ART combination treatment.

Conclusions:

  • The ART combination therapy represents a viable strategy to overcome TRAIL resistance in various solid tumors.
  • This approach activates the extrinsic apoptosis pathway, leading to cancer cell death.
  • Further development of TRAIL-induced apoptosis-based cancer therapies is warranted, with attention to specific resistance mechanisms.

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