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Inhibition of P-glycoprotein functionality by vandetanib may reverse cancer cell resistance to doxorubicin

C Jovelet1, J Bénard, F Forestier

  • 1Univ Paris-sud 11, Faculté de Pharmacie, Laboratoire de Pharmacie Clinique EA4123, Chatenay-Malabry, France. cecile.jovelet@u-psud.fr

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
|April 10, 2012
PubMed

Insights

Vandetanib inhibits P-glycoprotein (P-gp) functionality, reversing multidrug resistance in cancer cells. This tyrosine kinase inhibitor enhances doxorubicin efficacy by blocking P-gp efflux in resistant cells.

Area of Science:

  • Pharmacology
  • Cancer Biology
  • Molecular Biology

Background:

  • P-glycoprotein (P-gp) is an ATP-binding cassette transporter that confers multidrug resistance (MDR) in cancer cells by effluxing hydrophobic drugs, reducing therapeutic efficacy.
  • Understanding P-gp's role in MDR is crucial for developing strategies to overcome treatment resistance.
  • Tyrosine kinase inhibitors, such as vandetanib, are used in cancer therapy.

Purpose of the Study:

  • To investigate the effect of vandetanib on P-glycoprotein functionality.
  • To determine if vandetanib can restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells.
  • To assess vandetanib's potential in combination therapy for P-gp-mediated MDR.

Main Methods:

  • Established doxorubicin-resistant (IGROV1-DXR) and cisplatin-resistant (IGROV1-CDDP) cell lines from the parental IGROV1 cell line.
  • Assessed P-gp and MRP1 expression and functionality using western blotting and functional assays (rhodamine 123, calcein AM accumulation).
  • Treated resistant cell lines with vandetanib (2μM) for 24 hours and evaluated its impact on drug resistance and P-gp activity.

Main Results:

  • IGROV1-DXR cells overexpressed P-gp and exhibited resistance to doxorubicin, linked to functional P-gp activity.
  • Vandetanib treatment (24h) inhibited P-gp functionality, evidenced by increased rhodamine 123 and calcein AM accumulation.
  • Vandetanib reversed doxorubicin resistance in IGROV1-DXR cells but did not affect cisplatin resistance in IGROV1-CDDP cells.

Conclusions:

  • Vandetanib effectively inhibits P-glycoprotein functionality, reversing doxorubicin resistance in P-gp-overexpressing cancer cells.
  • Vandetanib demonstrates potential as a combination therapy agent to overcome P-gp-mediated multidrug resistance.
  • Further investigation is warranted for vandetanib's role in combination strategies against MDR cancers.

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