Document Detail

Inhibition of the P-glycoprotein- and multidrug resistance protein-mediated efflux of anthracyclines and calceinacetoxymethyl ester by PAK-104P.
MedLine Citation:
PMID:  10729360     Owner:  NLM     Status:  MEDLINE    
Multidrug resistance phenotype in mammalian cells is often correlated with overexpression of P-glycoprotein or Multidrug Resistance-Associated protein (MRP(1)). Both proteins are energy-dependent drug efflux pumps that efficiently reduce the intracellular accumulation and hence the cytotoxicity of many natural cytotoxins. Overexpression of these transporters by tumor cells is thought to be a significant factor in both intrinsic and acquired resistance to anticancer drugs. Consequently a great deal of interest is focused on identifying chemical agents that can either antagonise drug transport by these proteins or that can inhibit the proliferation of tumors cells despite the expression of these transporters. P-glycoprotein-mediated multidrug resistance is reversed by a variety of compounds, but surprisingly, few agents reverse the MRP(1)-mediated multidrug resistance. However, it has recently been shown that 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3, 2-dioxaphosphorinan-2-yl)-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P oxide (PAK-104P) was able to inhibit the P-glycoprotein and MRP(1)-mediated efflux of several compounds. Understanding of the interactions between transporters and multidrug resistance reversing agents is important in the design of more effective multidrug resistance modulators. We now examined the effect of PAK-104P on Pgp-and MRP1-mediated efflux of three anthracyclines, daunorubicin, pirarubicin, hydroxydoxorubicin and of calcein acetoxymethyl ester and calcein. Our data show that PAK-104P non-competitively inhibits the P-glycoprotein-mediated efflux of anthracycline derivatives and calcein acetoxymethyl ester with an inhibitory constant K(I)=0. 25+/-0.05 microM. PAK-104P also non-competitively inhibits the MRP(1)-mediated efflux of daunorubicin, pirarubicin, hydroxyrubicin, calcein acetoxymethyl ester and calcein. However, surprisingly, in this case the K(I) values obtained were very different ranging from 0.06 for hydroxyrubicin to 10 microM for calcein. These data strongly suggested the existence of two different mechanisms for the inhibition by PAK-104P of the MRP(1)-mediated efflux of molecules: a first mechanism, involving a low-affinity site for PAK-104P, and which would concern molecules such as calcein, cysteinyl leukotriene LCT(4) etc. whose efflux do not depend on glutathione. A second mechanism involving a high-affinity site for PAK-104P and which would concern molecules such as anthracyclines, calcein acetoxymethyl ester whose efflux depends on the presence of glutathione.
C Marbeuf-Gueye; M Salerno; P Quidu; A Garnier-Suillerot
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of pharmacology     Volume:  391     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-04-21     Completed Date:  2000-04-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  207-16     Citation Subset:  IM    
Laboratoire de Physicochimie Biomoléculaire et Cellulaire (ESA CNRS 7033), Université Paris Nord, 74 rue Marcel Cachin, Bobigny, France.
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MeSH Terms
ATP-Binding Cassette Transporters / physiology*
Antibiotics, Antineoplastic / metabolism*
Cyclic P-Oxides / pharmacology*
Daunorubicin / metabolism
Depression, Chemical
Doxorubicin / analogs & derivatives,  metabolism
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Epirubicin / analogs & derivatives,  metabolism
Fluoresceins / metabolism*
Multidrug Resistance-Associated Proteins
Neoplasm Proteins / physiology*
Nicotinic Acids / pharmacology*
P-Glycoprotein / physiology*
Tumor Cells, Cultured
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Antibiotics, Antineoplastic; 0/Cyclic P-Oxides; 0/Fluoresceins; 0/Multidrug Resistance-Associated Proteins; 0/Neoplasm Proteins; 0/Nicotinic Acids; 0/P-Glycoprotein; 131356-86-0/PAK 104P; 148504-34-1/calcein AM; 20830-81-3/Daunorubicin; 23214-92-8/Doxorubicin; 56420-45-2/Epirubicin; 72496-41-4/pirarubicin; 73113-90-3/3'-deamino-3'-hydroxydoxorubicin

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