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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.)

Introduction : Chemotherapy remains the only option for advanced cancer patients when other alternatives are not feasible. Nevertheless, the success rate of this type of therapy is often low due to intrinsic or acquired mechanisms of chemoresistance. Among them, drug extrusion from cancer cells through ATP-binding cassette (ABC) proteins plays an important role. ABC pumps are primary active transporters involved in the barrier and secretory functions of many healthy cells. Areas covered : In this review, we have used The Cancer Genome Atlas (TCGA) database to explore the relationship between the expression of the major ABC proteins involved in cancer chemoresistance in the most common types of cancer, and the drugs used in the treatment of these tumors that are substrates of these pumps. Expert opinion : From unicellular organisms to humans, several ABC proteins play a major role in detoxification processes. Cancer cells exploit this ability to protect themselves from cytostatic drugs. Among the ABC pumps, MDR1, MRPs and BCRP are able to export many antitumor drugs and are expressed in several types of cancer, and further up-regulated during treatment. This event results in the enhanced ability of tumor cells to reduce intracellular drug concentrations and hence the pharmacological effect of chemotherapy.

Introduction: Anticancer chemotherapy often faces the problem of intrinsic or acquired drug refractoriness due in part to efficient mechanisms of defense present or developed, respectively, in cancer cells. Owing to their polarity and/or high molecular weight, many cytostatic agents cannot freely cross the plasma membrane by simple diffusion and hence depend on SLC proteins to enter cancer cells. The downregulation of these transporters and the appearance of either inactivating mutations or aberrant splicing, hamper the possibility of anticancer drugs to interact with their intracellular targets. Areas covered: In addition to specific literature, we have revised Gene database of the NCBI PubMed resources and information publicly available at NIH 'The Cancer Genome Atlas' (TCGA) (update November 2018) to evaluate the relationship between the profile of expression of SLC transporters playing a major role in the transportome and accounting for drug uptake, in healthy and tumor tissue, and their ability to recognize as substrate several antitumor drugs frequently used in the treatment of different types of cancer, which could affect the overall response to chemotherapy based on regimens including these drugs. Expert commentary: Changes in the transportome may affect the overall response to chemotherapy based on drugs taken up by SLC transporters.