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Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways

Jamie F Lu1, Frederick Luk, Joyce Gong

  • 1School of Pharmacy, Graduate School of Health, University of Technology, Sydney, NSW 2007, Australia.

Pharmacological Research
|August 7, 2013
PubMed

Insights

Multidrug resistance (MDR) can spread between cancer cells through microparticles. This study shows functional MRP1 transfer via microparticles, impacting chemotherapy effectiveness and tumor resistance.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Multidrug resistance (MDR) significantly hinders chemotherapy efficacy in cancer treatment.
  • ATP-dependent transmembrane proteins, P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1), are key mediators of MDR by exporting chemotherapeutics.
  • Understanding MDR acquisition and dissemination is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the intercellular transfer of functional Multidrug Resistance-Associated Protein 1 (MRP1) via microparticles (MPs).
  • To explore the impact of microparticle-mediated transfer on drug sensitivity and resistance profiles in recipient cells.
  • To elucidate the role of microparticles in the dissemination of multidrug resistance traits in cancer.

Main Methods:

  • Overexpression of MRP1 in drug-resistant cells and subsequent shedding of microparticles (MPs).
  • Incubation of drug-sensitive recipient cells with shed MPs.
  • Assessment of P-gp and MRP1 functionality and drug resistance in recipient cells over time.
  • Analysis of the re-templating of resistance profiles by P-gp-dominant MPs on MRP1-dominant recipient cells.

Main Results:

  • Demonstrated successful transfer and time-dependent functionality of MRP1 into drug-sensitive leukemia cells via MPs.
  • Confirmed the transfer and functionality of P-gp in drug-sensitive recipient cells.
  • Observed that MPs from P-gp-dominant cells can alter pre-existing MRP1-dominant resistance profiles in recipient cells.

Conclusions:

  • Microparticle-mediated intercellular transfer is a mechanism for the acquisition and dissemination of functional MRP1.
  • This process contributes to the development of multidrug resistance phenotypes in cancer cells.
  • Findings suggest novel strategies targeting microparticle transfer for overcoming MDR and other acquired traits in oncology.
Keywords:
CtFCMIntercellular transferMDRMFIMPsMRP1MicroparticlesMultidrug Resistance-Associated Protein 1Multidrug resistanceP-glycoproteinP-gpPBCRe-templatingTrait dominancea.u.arbitrary unitscycle thresholdflow cytometrymean fluorescence intensitymicroparticlesmultidrug resistanceprobenecidqRT-PCRquantitative real-time PCR

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