Function and mechanism of pyronaridine: a new inhibitor of P-glycoprotein-mediated multidrug resistance

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Published on: May 9, 2025

Jing Qi1, Chun-Zheng Yang, Cai-Yun Wang

  • 1State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.

Acta Pharmacologica Sinica
|June 13, 2002
PubMed
Abstract

Insights

Pyronaridine (PND) effectively reverses multidrug resistance (MDR) in cancer cells by inhibiting P-glycoprotein (P-gp) function. This enhances chemotherapy by increasing drug accumulation and apoptosis, without affecting mdr1 gene expression.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) in cancer, particularly mediated by P-glycoprotein (P-gp), significantly limits chemotherapy efficacy.
  • K562/A02 (leukemia) and MCF7/ADR (breast cancer) cell lines exhibit MDR due to mdr1 gene expression.
  • Developing agents to overcome MDR is crucial for improving cancer treatment outcomes.

Purpose of the Study:

  • To investigate the effect of pyronaridine (PND) on reversing MDR in K562/A02 and MCF7/ADR cell lines.
  • To elucidate the mechanism by which PND affects MDR, including P-gp activity and drug accumulation.

Main Methods:

  • Cell viability was assessed using MTT assays after treatment with doxorubicin (DOX) alone or in combination with PND.
  • Intracellular DOX and rhodamine 123 (Rh123) accumulation were measured by spectrofluorometry.
  • P-gp activity was evaluated by monitoring Rh123 extrusion.
  • Apoptosis and mdr1 gene expression were analyzed via flow cytometry and RT-PCR, respectively.

Main Results:

  • PND demonstrated moderate cytotoxicity across tested cell lines.
  • PND significantly enhanced the antiproliferative and pro-apoptotic effects of DOX on MDR cells in a concentration-dependent manner.
  • Co-administration of PND increased intracellular DOX and Rh123 accumulation in MDR cells.
  • PND did not alter mdr1 gene expression in the studied MDR cell lines.

Conclusions:

  • Pyronaridine (PND), a third-generation P-gp inhibitor, effectively reverses multidrug resistance in K562/A02 and MCF7/ADR cell lines.
  • PND's mechanism involves direct inhibition of P-gp function, leading to increased intracellular drug levels and enhanced chemosensitivity.
  • PND represents a promising therapeutic strategy for overcoming P-gp-mediated MDR in certain cancers.

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