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

Cancer Res. 1996 Dec 1;56(23):5351-5.

Abstract

Overexpression of the multidrug resistance-associated protein (MRP) gene has been implicated in the resistance of tumor cell lines to a wide array of chemotherapeutic agents, but its normal physiological function(s) remains unknown. We have compared the sensitivity to chemotherapeutic drugs and toxins of wild-type W9.5 embryonic stem cells (ES) and of single and double MRP gene knockout cells derived therefrom. MRP expression was totally abrogated in the double knockout cell line and partially abrogated in the single knockout cell line. Reverse transcription-PCR analyses demonstrated that the MDR1, MDR2, and MDR3 genes were not expressed in either wild-type or MRP knock-out cells. The cytotoxic activities of etoposide, teniposide, vincristine, doxorubicin, daunorubicin, and sodium arsenite were significantly greater in double knockout cells than in parental wild-type ES cells; single knockout ES cells displayed an intermediate level of sensitivity. In contrast, no difference in sensitivity to colchicine and 1-beta-D-arabinofuranosylcytosine existed between the cell lines. Etoposide accumulation in double knockout ES cells was 2-fold higher than in wild-type ES cells. These findings indicate that baseline MRP expression has the capacity to exert a protective role against the toxicity of multiple chemotherapeutic agents and natural toxins.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • ATP-Binding Cassette Transporters / physiology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Arsenites / pharmacology
  • Cell Line
  • Colchicine / pharmacology
  • Cytarabine / pharmacology
  • Daunorubicin / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Etoposide / pharmacology
  • Gene Targeting*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins
  • Sodium Compounds / pharmacology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Teniposide / pharmacology
  • Vincristine / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Arsenites
  • Multidrug Resistance-Associated Proteins
  • Sodium Compounds
  • Cytarabine
  • sodium arsenite
  • Vincristine
  • Etoposide
  • Doxorubicin
  • Teniposide
  • multidrug resistance protein 3
  • Colchicine
  • Daunorubicin

Associated data

  • GENBANK/L05628