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Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

A M Calcagno1, J M Fostel, K K W To

  • 1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA.

British Journal of Cancer
|April 3, 2008
PubMed

Insights

Low-dose doxorubicin rapidly induces multidrug resistance (MDR) in cancer cells. This MDR is mediated by ABCG2 transporter upregulation through epigenetic changes, suggesting early mechanisms of resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Multidrug resistance (MDR) in cancer impacts treatment efficacy.
  • ATP binding cassette (ABC) transporters are linked to MDR, but their regulation is unclear.
  • Understanding MDR mechanisms can improve cancer therapy.

Purpose of the Study:

  • To investigate MDR development under clinically relevant, low-dose drug exposure.
  • To identify the specific ABC transporter involved in early-stage MDR.
  • To elucidate the regulatory mechanisms behind MDR induction.

Main Methods:

  • Selected breast, ovarian, and colon cancer cells using low-dose doxorubicin (14-21 nM) for 10 days.
  • Quantified ABCG2 expression at mRNA and protein levels.
  • Utilized RNA interference to confirm ABCG2's role in drug resistance.
  • Assessed histone acetylation and histone deacetylase 1 (HDAC1) association with the ABCG2 promoter.

Main Results:

  • Single-step, low-dose doxorubicin exposure induced MDR in multiple cancer cell lines.
  • Overexpression of ABCG2 was observed at both mRNA and protein levels.
  • ABCG2 was confirmed as the sole mediator of drug resistance in this model.
  • Epigenetic modifications, specifically histone hyperacetylation and reduced HDAC1 binding, were linked to ABCG2 upregulation.

Conclusions:

  • Low-dose, short-term doxorubicin exposure can rapidly induce MDR via ABCG2.
  • Epigenetic changes, including histone modifications, play a critical role in early MDR development.
  • ABCG2 may be an early mediator of MDR, offering potential therapeutic targets.

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