Abstract
The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.
Highlights
The two most frequent liver cancers, i.e., hepatocellular carcinoma (HCC), followed in the order of incidence by cholangiocarcinoma (CCA), are extremely resistant to pharmacological treatment [1].The mechanism of action of drugs used to treat these patients involves the interaction with their molecular targets, which, in most cases, are located intracellularly and, require their entrance across the plasma membrane
Since some transporters are differentially expressed in CCA and HCC, some attempts have been made to use them as biomarkers in diagnosis and prognosis and, even when they are expressed in both tumoral cholangiocytes and hepatocytes, they can be useful as targets to develop strategies aimed at sensitizing tumor cells to chemotherapy, either by increasing the uptake or reducing the export of anticancer drugs
Among members of the family ABCB of the ATP-binding cassette (ABC) proteins, the high expression of P-glycoprotein or multidrug resistance protein 1 (MDR1, gene symbol ABCB1) detected by immunohistochemistry in HCC was associated with a bad prognosis [24,25]; this pump has been proposed as a valuable biomarker of prognosis in gallbladder cancer [26]
Summary
The two most frequent liver cancers, i.e., hepatocellular carcinoma (HCC), followed in the order of incidence by cholangiocarcinoma (CCA), are extremely resistant to pharmacological treatment [1]. In aqueous solution, most of these drugs are electrically charged and, are not able to freely diffuse across the lipid bilayer, they must enter cancer cells through plasma membrane transporters These proteins belong to the solute carrier (SLC) superfamily of proteins, which, in humans, is formed by more than 400 members organized into 65 families. They share a structure characterized by a variable number of transmembrane domains connected by intracellular and extracellular loops. Several efflux pumps are involved in lowering the intracellular concentration of active agents by favoring the exit of the drugs Most of these proteins are primary transporters driven by the energy generated during ATP hydrolysis and belong to the superfamily of ATP-binding cassette (ABC) proteins. Since some transporters are differentially expressed in CCA and HCC, some attempts have been made to use them as biomarkers in diagnosis and prognosis and, even when they are expressed in both tumoral cholangiocytes and hepatocytes, they can be useful as targets to develop strategies aimed at sensitizing tumor cells to chemotherapy, either by increasing the uptake or reducing the export of anticancer drugs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
