Oncotarget

Research Papers:

Usefulness of the MRP2 promoter to overcome the chemoresistance of gastrointestinal and liver tumors by enhancing the expression of the drug transporter OATP1B1

Elisa Herraez, Laura Sanchez-Vicente, Rocio I.R. Macias, Oscar Briz and Jose J.G. Marin _

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Oncotarget. 2017; 8:34617-34629. https://doi.org/10.18632/oncotarget.16119

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Abstract

Elisa Herraez1,2,*, Laura Sanchez-Vicente1,*, Rocio I.R. Macias1,2, Oscar Briz1,2,** and Jose J.G. Marin1,2,**

1Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain

2Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

*Both authors contributed equally as first author to this work

**Both authors contributed equally as senior author to this work

Correspondence to:

Jose J.G. Marin, email: jjgmarin@usal.es

Keywords: ABC proteins, colon cancer, gene therapy, drug targeting, drug transporter

Received: December 29, 2016    Accepted: February 07, 2017    Published: March 11, 2017

ABSTRACT

Tumor response to chemotherapy is often limited by drug export through ABC proteins. To overcome this problem, here we have investigated the usefulness of inducing the expression of the multidrug uptake transporter OATP1B1 under the control of the MRP2 promoter (MRP2pr). Human hepatoma cells (Alexander) were transfected with MRP2pr fragments of different length fused to the firefly luciferase ORF in order to select the shortest fragment with the highest response to dexamethasone, which was subsequently used to generate the chimeric construct MRP2pr-OATP1B1-V5. Hepatoma cells transduced with MRP2pr-OATP1B1-V5 resulted in dexamethasone-sensitive inducible OATP1B1 expression and enhanced selective antitumor response to OATP1B1 substrates (paclitaxel, Bamet-R2 and Bamet-UD2). In human colon cancer cells LS174T/R, used as a model of endogenous chemoresistance due to MRP2 overexpression, MRP2pr-OATP1B1 induced OATP1B1 expression together with chemosensitivity to OATP1B1 substrates. In nude mice, xenografted tumors formed by LS174T/R cells transduced with MRP2pr-OATP1B1 plus treatment with dexamethasone were markedly sensitized to Bamet-UD2. In conclusion, the induced expression of anticancer drug uptake transporters, under the control of promoters of ABC proteins involved in chemoresistance, constitutes an interesting approach to overcome the poor response of cancer to chemotherapy due to reduced drug uptake and/or enhanced drug export.


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