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Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells

C Friesen1, S Fulda, K M Debatin

  • 1Hematology/Oncology, University Children's Hospital, and Division of Molecular Oncology, German Cancer Research Center, Heidelberg.

Leukemia
|November 22, 1997
PubMed

Insights

Chemotherapy resistance in cancer cells is partly due to a faulty CD95 receptor system. Restoring CD95 signaling may improve treatment effectiveness for leukemia and neuroblastoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Pathways

Background:

  • The mechanisms underlying tumor cell sensitivity and resistance to chemotherapy are not fully understood.
  • Anticancer drugs induce apoptosis (programmed cell death) in sensitive tumors.
  • The CD95 receptor/ligand (CD95/CD95-L) system was previously identified as crucial for drug-induced apoptosis.

Purpose of the Study:

  • To investigate the role of the CD95 system in chemotherapy-induced apoptosis in primary leukemia cells.
  • To identify mechanisms of resistance to chemotherapy and the CD95 system in leukemia and neuroblastoma.

Main Methods:

  • Treatment of primary leukemia cells and resistant cell lines with chemotherapeutic agents (doxorubicin, methotrexate, cytarabine).
  • Assessment of apoptosis induction via CD95 system activation.
  • Analysis of CD95 and CD95-L expression levels.
  • Evaluation of poly(ADP-ribose)polymerase (PARP) cleavage as a marker of apoptosis.

Main Results:

  • Therapeutic drug concentrations induced apoptosis via CD95 system activation in primary leukemia cells.
  • CD95-resistant and doxorubicin-resistant cells exhibited cross-resistance to cell death induction.
  • Drug-resistant cells showed down-regulated CD95 expression and blocked CD95-L up-regulation.
  • PARP cleavage occurred in sensitive but not resistant cells after CD95 triggering or drug treatment.

Conclusions:

  • An intact CD95 system is critical for determining sensitivity or resistance to anticancer therapy.
  • Non-multi-drug resistance (non-MDR) mechanisms are involved in resistance to chemotherapy.
  • Targeting the CD95 pathway may offer new strategies to overcome chemotherapy resistance.

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