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1. Eur J Pharm Sci. 2012 Mar 30. [Epub ahead of print]

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

Jovelet C, Bénard J, Forestier F, Farinotti R, Bidart JM, Gil S.

Univ Paris-sud 11, Faculté de Pharmacie, Laboratoire de Pharmacie Clinique
EA4123, Chatenay-Malabry, France.

P-glycoprotein belongs to the ATP binding cassette transporters, responsible for
the multidrug resistance of cancer cells. These transporters efflux hydrophobic
drugs outside cells and decrease their therapeutic efficacy. The aim of this
study was to investigate the effect of vandetanib, an oral tyrosine kinase
inhibitor of EGFR, VEGFR 2 and RET kinases, on the functionality of P-gp after a
24h-treatment at therapeutic concentration (2μM), and its ability to increase the
cytotoxicity of chemotherapeutic agents in multidrug resistance cancer cells. In
this study we found that IGROV1-DXR and IGROV1-CDDP cells were resistant to
doxorubicin and cisplatin respectively, compare to parental cell line IGROV1. The
parental sensitive and the two resistant cell lines similarly expressed MRP1 and
did not express BCRP. Moreover, in contrast to the IGROV1 and IGROV1-CDDP cells,
IGROV1-DXR cell line overexpressed P-gp. Functional activity studies demonstrated
that MRP1 was not functional and the MDR phenotype in IGROV1-DXR cells was linked
to P-gp functionality. Results also showed that vandetanib reversed resistance to
doxorubicin in IGROV1-DXR cells, but not to cisplatin in IGROV1-CDDP cells. After
24h of treatment, vandetanib increased the accumulation of rhodamine 123 and
calcein AM, demonstrating a functional inhibition of the transporter. In
IGROV1-DXR cell line, vandetanib reverse resistance to doxorubicin by inhibiting
the functionality of P-gp. In conclusion, vandetanib should be an option for drug
combination in patients already developing a P-gp mediated multidrug resistance.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22484209 [PubMed - as supplied by publisher]