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Lignans and norlignans inhibit multidrug resistance protein 1 (MRP1/ABCC1)-mediated transport

Anna Wróbel1, Patrik Eklund, Malgorzata Bobrowska-Hägerstrand

  • 1Institute of Physics, Wrocław University of Technology, Wybrzeże Wyspańskiego 27, 50-370 Wrocław, Poland. anna.wrobel@pwr.wroc.pl

Anticancer Research
|December 1, 2010
PubMed
Abstract

Insights

Plant lignans and norlignans effectively inhibit multidrug resistance protein 1 (MRP1) transport in human red blood cells. These compounds show potential for reversing multidrug resistance in cancer therapy without causing toxicity.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Multidrug resistance protein 1 (MRP1/ABCC1) is a key efflux pump contributing to multidrug resistance in various cancers.
  • Developing efficient and non-toxic MRP1 inhibitors is crucial for sensitizing cancer cells to chemotherapy.
  • Human erythrocytes serve as a valuable model for identifying MRP1 inhibitors due to the presence of MRP1 in their membranes.

Purpose of the Study:

  • To evaluate the inhibitory potential of plant lignans and norlignans against MRP1-mediated transport.
  • To investigate the structure-activity relationships of these compounds in inhibiting MRP1.
  • To assess the safety profile of active lignans and norlignans by examining their effects on erythrocyte integrity.

Main Methods:

  • Inhibition of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) transport from human erythrocytes was measured using a fluorometric assay.
  • Compounds were screened for their ability to induce haemolysis, alter erythrocyte shape, and cause phosphatidylserine (PS) exposure.
  • Structure-activity relationships were analyzed to identify key features for MRP1 inhibition.

Main Results:

  • Nine out of fourteen tested compounds (six norlignans, three lignans) inhibited BCPCF transport.
  • The most potent inhibitor, norlignan L1, exhibited an IC50 of 50 μM.
  • Inhibitory activity was enhanced by carbonyl groups at C-9, high oxidation, and ionizable carboxylic acid functions.
  • Active compounds were non-haemolytic and did not affect erythrocyte shape or PS exposure at tested concentrations.

Conclusions:

  • Plant-derived lignans and norlignans demonstrate significant potential as MRP1 inhibitors.
  • These compounds can effectively inhibit MRP1-mediated transport in human erythrocytes.
  • Further research into lignans and norlignans is warranted for their development as agents to reverse multidrug resistance.

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