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A cytotoxic ribonuclease reduces the expression level of P-glycoprotein in multidrug-resistant cell lines

Jessica Castro1, Marc Ribó, Teresa Puig

  • 1Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, Maria Aurèlia Campmany, 69, 17071, Girona, Spain.

Investigational New Drugs
|February 3, 2011
PubMed

Insights

A novel human ribonuclease variant, PE5, effectively reduces P-glycoprotein in multidrug-resistant cancer cells. This finding suggests PE5 as a potential therapeutic agent against drug resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Multidrug resistance (MDR) is a major challenge in cancer therapy.
  • P-glycoprotein (P-gp) overexpression is a key mechanism driving MDR.
  • Targeting P-gp offers a strategy to overcome drug resistance.

Purpose of the Study:

  • To investigate the effect of human pancreatic-ribonuclease variant PE5 on P-glycoprotein accumulation in MDR cells.
  • To evaluate the potential of PE5 as an anticancer agent against MDR phenotypes.

Main Methods:

  • Treatment of multidrug-resistant cell lines (NCI/H460-R, NCI/ADR-RES) with PE5.
  • Assessment of P-glycoprotein levels.
  • Glutathione S-transferase-л expression analysis.
  • Flow cytometry for functional confirmation.
  • Evaluation of synergistic cytotoxicity with doxorubicin.

Main Results:

  • PE5 significantly reduced P-glycoprotein levels in NCI/H460-R and NCI/ADR-RES cells.
  • Glutathione S-transferase-л expression remained unaffected by PE5.
  • PE5 demonstrated synergistic cytotoxicity with doxorubicin in NCI/ADR-RES cells.
  • PE5-induced reduction in P-gp may be linked to JNK underphosphorylation.

Conclusions:

  • PE5, a cytotoxic ribonuclease, decreases P-glycoprotein expression in MDR cancer cells.
  • PE5 exhibits anticancer activity and potential synergistic effects with chemotherapy in MDR contexts.
  • PE5 represents a promising therapeutic candidate for overcoming multidrug resistance.

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