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Using small molecules to overcome drug resistance induced by a viral oncogene

Inese Smukste1, Oneil Bhalala, Marco Persico

  • 1Department of Biological Sciences and Department of Chemistry, Columbia University, Fairchild Center, MC 2406, 1212 Amsterdam Avenue, New York, New York 10027, USA.

Cancer Cell
|February 14, 2006
PubMed

Insights

Researchers identified new compounds to overcome E6 oncogene drug resistance in colon cancer. These compounds, including novel indoxins, enhance doxorubicin

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The E6 oncogene contributes to drug resistance in various cancers, including colon cancer.
  • Doxorubicin is a chemotherapy agent whose efficacy can be limited by drug resistance mechanisms.

Purpose of the Study:

  • To identify small molecules that can overcome E6 oncogene-mediated drug resistance.
  • To elucidate the mechanisms by which these compounds potentiate chemotherapy.

Main Methods:

  • High-throughput screening of small molecules in isogenic cell lines.
  • Assays to measure drug lethality and target engagement.
  • Photolabeling strategies to identify compound targets.

Main Results:

  • Identified several classes of compounds potentiating doxorubicin lethality in E6-expressing colon cancer cells.
  • Discovered indoxins, a novel class of compounds, that upregulate topoisomerase IIalpha, enhancing doxorubicin's effect.
  • Identified a nuclear actin-related protein complex as a potential target of indoxins.

Conclusions:

  • Small molecule screening is effective for discovering strategies to overcome E6-mediated drug resistance.
  • Indoxins represent a promising new class of compounds for potentiating doxorubicin chemotherapy.
  • Targeting nuclear actin-related protein complexes may offer a novel therapeutic approach in E6-expressing cancers.

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