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Double knockout of the MRP gene leads to increased drug sensitivity in vitro

A Lorico1, G Rappa, R A Flavell

  • 1Department of Pharmacology and Developmental Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Cancer Research
|December 1, 1996
PubMed

Insights

The multidrug resistance-associated protein (MRP) gene protects cells from chemotherapy drugs. Knocking out the MRP gene increases sensitivity to several common chemotherapeutic agents and toxins.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • The multidrug resistance-associated protein (MRP) gene is linked to tumor cell resistance against chemotherapy.
  • The normal physiological role of the MRP gene is not well understood.

Purpose of the Study:

  • To investigate the physiological function of the MRP gene.
  • To compare the sensitivity of wild-type and MRP-deficient embryonic stem cells to various chemotherapeutic drugs and toxins.

Main Methods:

  • Generated single and double MRP gene knockout embryonic stem (ES) cell lines.
  • Assessed drug sensitivity using cytotoxic assays for etoposide, teniposide, vincristine, doxorubicin, daunorubicin, sodium arsenite, colchicine, and 1-beta-D-arabinofuranosylcytosine.
  • Quantified etoposide accumulation in wild-type and knockout cells.

Main Results:

  • Double MRP knockout cells showed significantly greater sensitivity to etoposide, teniposide, vincristine, doxorubicin, daunorubicin, and sodium arsenite compared to wild-type ES cells.
  • Single MRP knockout cells exhibited intermediate sensitivity.
  • No difference in sensitivity to colchicine and 1-beta-D-arabinofuranosylcytosine was observed.
  • Etoposide accumulation was 2-fold higher in double knockout cells.

Conclusions:

  • Baseline MRP gene expression provides a protective role against the toxicity of multiple chemotherapeutic agents and natural toxins.
  • MRP plays a significant role in cellular defense mechanisms against xenobiotics.

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