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Anticancer agents sensitize osteosarcoma cells to TNF-related apoptosis-inducing ligand downmodulating IAP family

Prisco Mirandola1, Ivonne Sponzilli, Giuliana Gobbi

  • 1Department of Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma, 43100 Parma, Italy.

International Journal of Oncology
|December 6, 2005
PubMed

Insights

Genotoxic drugs like Doxorubicin and Cisplatin sensitize resistant osteosarcoma cells to TNF-related apoptosis-inducing ligand (TRAIL) by downregulating X-IAP, not surface receptors. This suggests combining chemotherapy with TRAIL therapy may benefit osteosarcoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • TNF-related apoptosis-inducing ligand (TRAIL) typically induces cancer cell death.
  • Some cancer cells, like U2OS osteosarcoma cells, are resistant to TRAIL-induced apoptosis.
  • Chemotherapeutic drugs can overcome TRAIL resistance by altering receptor expression or intracellular pathways.

Purpose of the Study:

  • To investigate the mechanism by which Doxorubicin and Cisplatin sensitize TRAIL-resistant U2OS osteosarcoma cells.
  • To determine if sensitization involves surface TRAIL receptor modulation or intracellular signaling pathway changes.

Main Methods:

  • U2OS cells were treated with Doxorubicin and Cisplatin, followed by TRAIL exposure.
  • Surface expression of TRAIL death and decoy receptors was analyzed.
  • Intracellular levels of X-IAP and FLIP were assessed.
  • Small interfering RNA (siRNA) was used to selectively downregulate X-IAP and TRAIL-R2.

Main Results:

  • Doxorubicin and Cisplatin sensitized U2OS cells to TRAIL without altering surface TRAIL receptor levels.
  • These drugs specifically downmodulated X-IAP, but not FLIP.
  • Selective X-IAP downregulation via siRNA mimicked the sensitization effect of the drugs.
  • TRAIL-R2 downregulation by siRNA abolished TRAIL-induced apoptosis in drug-treated cells.

Conclusions:

  • Doxorubicin and Cisplatin sensitize osteosarcoma cells to TRAIL by inhibiting intracellular signaling via X-IAP, not by modulating surface receptors.
  • Targeting X-IAP represents a potential therapeutic strategy to enhance TRAIL-based cancer treatments.
  • Combined genotoxin-based chemotherapy and TRAIL therapy may offer a significant advantage for treating osteosarcoma.

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