1. Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3.
- Author
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Asensio M, Briz O, Herraez E, Perez-Silva L, Espinosa-Escudero R, Bueno-Sacristan D, Peleteiro-Vigil A, Hammer H, Pötz O, Kadioglu O, Banales JM, Martinez-Chantar ML, Avila MA, Macias RIR, Efferth T, Marin JJG, and Lozano E
- Subjects
- Humans, Animals, Cell Line, Tumor, HEK293 Cells, Mice, Nude, Mice, Molecular Docking Simulation, Cholangiocarcinoma drug therapy, Cholangiocarcinoma pathology, Cholangiocarcinoma metabolism, Cholangiocarcinoma genetics, Multidrug Resistance-Associated Proteins metabolism, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins antagonists & inhibitors, Bile Duct Neoplasms drug therapy, Bile Duct Neoplasms pathology, Bile Duct Neoplasms metabolism, Bile Duct Neoplasms genetics, Drug Resistance, Neoplasm drug effects, Antineoplastic Agents pharmacology, Xenograft Model Antitumor Assays, Cisplatin pharmacology
- Abstract
Aims: Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance., Methods: Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo., Results: High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin., Conclusions: Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jose J.G. Marin reports financial support was provided by Carlos III Health Institute. Jose J.G. Marin reports financial support was provided by Spanish Ministry of Science and Innovation. Jose J.G. Marin reports financial support was provided by Junta de Castilla y León, Consejería de Educación. Jose J.G. Marin reports financial support was provided by Spanish Association Against Cancer Scientific Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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