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Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif

Ye, Siying, MacEachran, Daniel P., Hamilton, Joshua W., O'Toole, George A. and Stanton, Bruce A. 2008, Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif, American journal of physiology : cell physiology, vol. 295, no. 3, pp. 807-818, doi: 10.1152/ajpcell.00234.2008.

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Title Chemotoxicity of doxorubicin and surface expression of P-glycoprotein (MDR1) is regulated by the Pseudomonas aeruginosa toxin Cif
Author(s) Ye, Siying
MacEachran, Daniel P.
Hamilton, Joshua W.
O'Toole, George A.
Stanton, Bruce A.
Journal name American journal of physiology : cell physiology
Volume number 295
Issue number 3
Start page 807
End page 818
Total pages 12
Publisher American Physiological Society
Place of publication Bethesda, Md.
Publication date 2008-09
ISSN 0363-6143
1522-1563
Keyword(s) multidrug resistance
adenosine triphosphate-binding cassette transporter
cystic fibrosis transmembrane conductance regulator
Madin-Darby canine kidney
Caco-2
Summary P-glycoprotein (Pgp), a member of the adenosine triphosphate-binding cassette (ABC) transporter superfamily, is a major drug efflux pump expressed in normal tissues, and is overexpressed in many human cancers. Overexpression of Pgp results in reduced intracellular drug concentration and cytotoxicity of chemotherapeutic drugs and is thought to contribute to multidrug resistance of cancer cells. The involvement of Pgp in clinical drug resistance has led to a search for molecules that block Pgp transporter activity to improve the efficacy and pharmacokinetics of therapeutic agents. We have recently identified and characterized a secreted toxin from Pseudomonas aeruginosa, designated cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif). Cif reduces the apical membrane abundance of CFTR, also an ABC transporter, and inhibits the CFTR-mediated chloride ion secretion by human airway and kidney epithelial cells. We report presently that Cif also inhibits the apical membrane abundance of Pgp in kidney, airway, and intestinal epithelial cells but has no effect on plasma membrane abundance of multidrug resistance protein 1 or 2. Cif increased the drug sensitivity to doxorubicin in kidney cells expressing Pgp by 10-fold and increased the cellular accumulation of daunorubicin by 2-fold. Thus our studies show that Cif increases the sensitivity of Pgp-overexpressing cells to doxorubicin, consistent with the hypothesis that Cif affects Pgp functional expression. These results suggest that Cif may be useful to develop a new class of specific inhibitors of Pgp aimed at increasing the sensitivity of tumors to chemotherapeutic drugs, and at improving the bioavailability of Pgp transport substrates.
Language eng
DOI 10.1152/ajpcell.00234.2008
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2008, American Physiological Society
Persistent URL http://hdl.handle.net/10536/DRO/DU:30040954

Document type: Journal Article
Collection: School of Medicine
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