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Factors determining sensitivity and resistance of tumor cells to arsenic trioxide

Serkan Sertel1, Margaret Tome, Margaret M Briehl

  • 1Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.

Plos One
|May 17, 2012
PubMed

Insights

Arsenic trioxide is a potent anti-cancer agent, but its effectiveness varies. This study identifies molecular factors influencing tumor cell sensitivity and resistance to arsenic trioxide, revealing a multi-factorial response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Arsenic trioxide demonstrates significant efficacy in treating acute promyelocytic leukemia.
  • Understanding molecular mechanisms of arsenic trioxide sensitivity and resistance is crucial for broader cancer therapy.

Purpose of the Study:

  • To identify molecular determinants of sensitivity and resistance in various tumor cell lines treated with arsenic trioxide.
  • To correlate gene expression profiles with cellular responses to arsenic trioxide.

Main Methods:

  • Utilized a panel of NCI cell lines to assess cytotoxicity of arsenic trioxide and other arsenicals.
  • Employed transcriptome-wide microarray analysis and bioinformatic approaches (COMPARE, hierarchical clustering, Ingenuity pathway analysis) to correlate gene expression with IC(50) values.
  • Investigated the role of specific genes (catalase, thioredoxin, bcl-2) and multidrug resistance transporters (MDR1, MRP1, BCRP) in cellular response.

Main Results:

  • Arsenic trioxide exhibited the highest cytotoxicity among tested arsenicals.
  • Signaling pathways involving p53, integrin-linked kinase, and actin cytoskeleton were significantly associated with cellular response.
  • Overexpression of catalase, thioredoxin, or bcl-2 conferred increased resistance to arsenic trioxide.
  • Multidrug-resistant cell lines were not cross-resistant to arsenic trioxide.

Conclusions:

  • Tumor cell response to arsenic trioxide is influenced by multiple molecular factors.
  • Specific gene expression patterns and certain resistance-associated genes play a role in modulating arsenic trioxide efficacy.

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