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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.)

Cancer drug resistance constitutes a severe limitation for the satisfactory outcome of these patients. This is a complex problem due to the co-existence in cancer cells of multiple and synergistic mechanisms of chemoresistance (MOC). These mechanisms are accounted for by the expression of a set of genes included in the so-called resistome, whose effectiveness often leads to a lack of response to pharmacological treatment. Additionally, genetic variants affecting these genes further increase the complexity of the question. This review focuses on a set of genes encoding members of the transportome involved in drug uptake, which have been classified into the MOC-1A subgroup of the resistome. These proteins belong to the solute carrier (SLC) superfamily. More precisely, we have considered here several members of families SLC2, SLC7, SLC19, SLC22, SLCO, SLC28, SLC29, SLC31, SLC46, and SLC47 due to the impact of their expression and genetic variants in anticancer drug uptake by tumor cells or, in some cases, general bioavailability. Changes in their expression levels and the appearance of genetic variants can contribute to the Darwinian selection of more resistant clones and, hence, to the development of a more malignant phenotype. Accordingly, to address this issue in future personalized medicine, it is necessary to characterize both changes in resistome genes that can affect their function. It is also essential to consider the time-dependent dimension of these features, as the genetic expression and the appearance of genetic variants can change during tumor progression and in response to treatment., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2024.)

Background and Aims: A limitation for the treatment of unresectable cholangiocarcinoma (CCA) is its poor response to chemotherapy, which is partly due to reduction of intracellular levels of anticancer drugs through ATP-binding cassette (ABC) pumps. Low expression of SOX17 (SRY-box containing gene 17), a transcription factor that promotes biliary differentiation and phenotype maintenance, has been associated with cholangiocyte malignant transformation. Whether SOX17 is also involved in CCA chemoresistance is investigated in this study., Approach and Results: SOX17 expression in human CCA cells (EGI-1 and TFK-1) selectively potentiated cytotoxicity of SN-38, 5-fluorouracil and mitoxantrone, but not that of gemcitabine, capecitabine, cisplatin, or oxaliplatin. The analysis of the resistome by TaqMan low-density arrays revealed changes affecting primarily ABC pump expression. Single-gene quantitative real-time PCR, immunoblot, and immunofluorescence analyses confirmed that MRP3 (multidrug resistance associated protein 3), which was highly expressed in CCA human tumors, was down-regulated in SOX17-transduced CCA cells. The substrate specificity of this pump matched that of SOX17-induced in vitro selective chemosensitization. Functional studies showed lower ability of SOX17-expressing CCA cells to extrude specific MRP3 substrates. Reporter assay of MRP3 promoter (ABCC3pr) revealed that ABCC3pr activity was inhibited by SOX17 expression and SOX2/SOX9 silencing. The latter was highly expressed in CCA. Moreover, SOX2/9, but not SOX17, induced altered electrophoretic mobility of ABCC3pr, which was prevented by SOX17. The growth of CCA tumors subcutaneously implanted into immunodeficient mice was inhibited by 5-fluorouracil. This effect was enhanced by co-treatment with adenoviral vectors encoding SOX17., Conclusions: SOX9/2/17 are involved in MRP3-mediated CCA chemoresistance. Restored SOX17 expression, in addition to its tumor suppression effect, induces selective chemosensitization due to MRP3 down-regulation and subsequent intracellular drug accumulation., (© 2020 by the American Association for the Study of Liver Diseases.)

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.

Owing to intrinsic and acquired chemoresistance, the response of gastric adenocarcinoma (GAC) to chemotherapy is very poor. Here we have investigated the role of transportome in reducing the intracellular content of anticancer drugs and conferring multidrug resistance (MDR) phenotype. Tumors specimens and paired adjacent tissue were analyzed to determine the MDR signature by TaqMan Low-Density Arrays and single-gene qPCR. Strategies of sensitization were evaluated in vitro using the GAC-derived cell line AGS and in vivo using a subcutaneous xenograft model in immunodeficient nude mice. Several transporters involved in drug uptake and export, which are present in healthy stomach, were highly expressed in GAC. In contrast, the cancer-type OATP1B3 was almost exclusively expressed in tumor tissue. The transportome profile varied depending on tumor anatomical location, differentiation, and stage. Immunofluorescence analysis revealed high MRP1 and MRP4 expression at the plasma membrane of tumor cells as well as AGS cells in culture, in which MRP inhibition resulted in selective sensitization to cytotoxic MRP substrates, such as sorafenib, docetaxel, etoposide, and doxorubicin. In mice with subcutaneous tumors formed by AGS cells, sorafenib alone failed to prevent tumor growth. In contrast, this drug induced a marked inhibitory effect when it was co-administered with diclofenac. In conclusion, MRP1 and MRP4 play an important role in the lack of response of GAC to drugs that are transported by these export pumps. Moreover, agents, such as sorafenib, considered at present useless to treat GAC, may become active antitumor drugs when co-administered with non-toxic MRP inhibitors, such as diclofenac., (Copyright © 2019 Elsevier Inc. 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.

A significant risk to the food chain is the presence of noxious pollutants in the feeds of animals whose products are used in human nutrition. Consequently, analytical methods and biosensors have been developed to detect these types of contaminates in feeds. Here we have evaluated whether the expression of TolC, a promiscuous component of several ATP-dependent efflux pumps in E. coli, up-regulated in response to chemical stress, could be a useful biomarker for this aim. Changes in TolC expression in response to toxic compounds, with different abilities to induce DNA damage, were determined using two E. coli strains with (DH5α) and without (BL21(DE3)) inactivating mutation in RecA gene. Deoxycholic acid and potassium dichromate up-regulated TolC in both strains. In contrast, cisplatin-induced TolC up-regulation was abolished in the absence of a functional RecA. When the effect of several insecticides, herbicides, antibiotics and common soil pollutants on TolC expression was analyzed, a relationship between toxicity and their ability to up-regulate TolC was observed. However, this was not a general event because the insecticide α-cipermetrin induced a reduction in cell viability, which was not accompanied by TolC up-regulation. In contrast, the soil pollutant benzene was able to stimulate TolC expression at non-toxic concentrations. When this test was used to analyze aqueous extracts from different feedstuffs, up-regulation of TolC was found in the absence of cell toxicity and was even accompanied by enhanced cell viability. In conclusion, TolC expression is partly dependent on the integrity of the RecA/LexaA system. Although toxic compounds up-regulate TolC in a dose-dependent manner, this response is also activated by non-toxic agents. Thus, owing to its poor specificity regardless of its sensitivity, the use of TolC up-regulation in E. coli to detect the presence of toxic pollutants in conventional and unconventional sources of nutrients for ruminant feeding requires supplementary biomarkers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.