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Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL

Alena Vaculova1, Vitaliy Kaminskyy, Elham Jalalvand

  • 1Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.

Molecular Cancer
|April 27, 2010
PubMed
Abstract

Insights

Doxorubicin and etoposide enhance TRAIL-induced apoptosis in small cell lung cancer (SCLC) cells. This combination therapy overcomes TRAIL resistance by modulating caspase-8 and related apoptotic pathways, offering a promising strategy for SCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise as an anti-cancer agent due to its selective apoptosis induction.
  • Many cancer cells, including small cell lung cancer (SCLC), exhibit resistance to TRAIL monotherapy, limiting its clinical efficacy.
  • Developing strategies to overcome TRAIL resistance is crucial for enhancing anti-cancer treatments.

Purpose of the Study:

  • To investigate the potential of doxorubicin and etoposide in sensitizing SCLC cells to TRAIL-induced apoptosis.
  • To elucidate the molecular mechanisms underlying drug-mediated sensitization to TRAIL in SCLC.

Main Methods:

  • Treatment of SCLC cells with doxorubicin and/or etoposide in combination with TRAIL.
  • Assessment of apoptosis induction via caspase activation and Western blotting.
  • Analysis of cell surface and total DR5 protein levels.
  • Evaluation of caspase-8, cFLIP, Bid, Bax, and cytochrome c expression and activation.

Main Results:

  • Doxorubicin and etoposide significantly sensitized SCLC cells expressing caspase-8 to TRAIL-induced apoptosis.
  • Combined treatment led to increased DR5 protein, cFLIPL cleavage, decreased cFLIPS, and robust caspase-8 activation.
  • Mitochondrial pathway involvement was confirmed by enhanced Bid cleavage, Bax activation, and cytochrome c release.
  • Caspase-8 activation occurred upstream of the mitochondrial pathway and effector caspases.

Conclusions:

  • Doxorubicin and etoposide are effective sensitizers of SCLC cells expressing caspase-8 to TRAIL treatment.
  • This combination strategy holds significant therapeutic applicability for SCLC patients.
  • Targeting apoptotic pathways with combined therapies can overcome drug resistance in SCLC.

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