Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein

Br J Cancer. 1997;75(6):810-5. doi: 10.1038/bjc.1997.145.


Decreased accumulation of the fluorescent dye BCECF [2', 7'-bis-(2-carboxyethyl)-5-(6)- carboxyfluorescein] characterized murine and human multidrug-resistant cell lines overexpressing the multidrug resistance protein (MRP). Indomethacin (10 microM), a known cyclo-oxygenase and glutathione-S-transferase inhibitor as well as a modulator of anion transport, increased accumulation and blocked efflux of BCECF in MRP-expressing murine and human cells. The drug did not affect P-glycoprotein (P-gp)-mediated export of rhodamine 123. The indomethacin effect on BCECF efflux was not reversed by the addition of exogenous prostaglandins, suggesting that the drug acts by a mechanism other than decreasing prostaglandin synthesis. Indomethacin also increased multidrug susceptibility of both murine and human cell lines overexpressing MRP, but not those displaying P-gp-associated resistance. In addition, indomethacin modulated the decreased vincristine accumulation in cells expressing MRP, but not in those expressing P-gp. These data suggest that indomethacin is a specific inhibitor of MRP, possibly functioning by inhibition of glutathione-S-transferase or, alternatively, by direct competition with the drug at the transport site.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / drug effects*
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents, Phytogenic / metabolism
  • Drug Resistance, Multiple*
  • Fluoresceins / metabolism*
  • Fluorescent Dyes / metabolism
  • HL-60 Cells / drug effects
  • HL-60 Cells / metabolism
  • Humans
  • Indomethacin / pharmacology*
  • Leukemia, Erythroblastic, Acute / metabolism
  • Mice
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / metabolism
  • Rhodamines / metabolism
  • Tumor Cells, Cultured / metabolism
  • Vincristine / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Phytogenic
  • Fluoresceins
  • Fluorescent Dyes
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Rhodamines
  • 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester
  • Vincristine
  • Indomethacin