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Correlating the Reversal of Multidrug Resistance in Cancers by Novel P‐glycoprotein Inhibitors to the Expression of ABC Transporters
Author(s) -
Sunshine Alexis L.,
Follit Courtney A.,
Marchesseault Collette,
Wise John G.,
Vogel Pia D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.848.2
Subject(s) - multiple drug resistance , atp binding cassette transporter , p glycoprotein , transporter , efflux , cytosol , drug resistance , cancer cell , extracellular , cell culture , transmembrane protein , function (biology) , chemistry , intracellular , drug , multidrug resistance associated proteins , plasma protein binding , biochemistry , biology , pharmacology , microbiology and biotechnology , cancer , enzyme , gene , genetics , receptor
P‐glycoprotein (P‐gp) is a transmembrane protein that has evolved to eliminate toxic compounds from cells. It functions by using the hydrolysis of ATP to generate a conformational change that physically pushes xenobiotics that are bound in the drug‐binding domain of P‐gp from the cytosolic side of the membrane into the extracellular space. This broad functionality of the pump relies on the inherently non‐discriminating character of multiple binding sites within the drug binding domains and allows P‐gp to transport a variety of substances including most currently approved chemotherapeutics. Overexpression of P‐gp in a cell, therefore, results in a remarkable resistance to the presence of toxic chemicals, even enabling cancerous cells to survive chemotherapy treatments, which ultimately renders such therapy ineffective. It is possible, however, for an inhibitory agent to bind to P‐gp and to inactivate its function. In recent computational ultra‐high throughput searches followed by biochemical, biophysical and cell culture evaluations, we have identified several compounds that reverse multidrug resistance in cancer cells in culture (Brewer, F. K., Follit, C. A., Vogel, P. D., & Wise, J. G. (2014) Molecular pharmacology, 86(6), 716–726; Follit, C. A., Brewer, F. K., Wise, J. G., & Vogel, P. D. (2015) Pharmacology Research & Perspectives, 3(5) doi:10.1002/prp2.170). In the present study, we aim to extend these findings by quantifying the expression levels of P‐gp and other multidrug resistance proteins in various multi‐drug resistant cancer cell lines. Correlating the level of reversal of multidrug resistances with the level of expression of the various ABC transporter proteins that have been associated with the multidrug resistance phenotype, will allow us to determine the ABC transporter specificity of the discovered compounds. Such an approach may in the future be used to develop personalized medical treatment for patients with multi‐drug resistant cancers conferred by specific ABC transporters. Support or Funding Information This work is supported by NIH NIGMS [Grants R15‐GM094771‐01A1 and R15‐GM094771‐02] to PDV and JGW, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, New England Biolabs / Lynn McBee, the Hamilton Undergraduate Research Scholarship Program, and a private gift from Ms. Suzann Ruff of Dallas, Texas.