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Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin

Andrew S Goldsborough1, Misty D Handley, Andrés E Dulcey

  • 1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Journal of Medicinal Chemistry
|June 11, 2011
PubMed

Insights

Tiopronin selectively targets cancer cells with drug efflux pumps like P-glycoprotein (P-gp) and MRP1. This compound reduces P-gp and MRP1 protein levels, potentially overcoming multidrug resistance (MDR) in chemotherapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) is a significant obstacle in cancer chemotherapy.
  • Drug efflux pumps, such as P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1), are key mediators of MDR.

Purpose of the Study:

  • To investigate the selective toxicity of tiopronin against cancer cells overexpressing P-gp and MRP1.
  • To elucidate the mechanism by which tiopronin affects P-gp and MRP1 expression and function.

Main Methods:

  • Cell viability assays on cell lines expressing P-gp and MRP1.
  • Analysis of ABCB1 mRNA and P-gp protein levels following tiopronin treatment.
  • Assessment of cell sensitization to chemotherapy drugs (doxorubicin, paclitaxel).
  • Synthesis and evaluation of tiopronin analogues.

Main Results:

  • Tiopronin exhibited selective toxicity towards cells expressing P-gp and MRP1.
  • Tiopronin treatment led to decreased ABCB1 mRNA and P-gp protein levels, and reduced MRP1 protein.
  • Tiopronin sensitized P-gp-expressing cells to doxorubicin and paclitaxel.
  • The thiol group of tiopronin was crucial for its observed effects.

Conclusions:

  • Tiopronin demonstrates potential as a novel agent to overcome MDR by downregulating P-gp and MRP1.
  • The thiol functional group is essential for tiopronin's activity, suggesting a specific mechanism of action.
  • Further development of tiopronin analogues could lead to targeted therapies for resistant cancers.

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