OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1.

High-affinity uptake of natural nucleosides as well as nucleoside derivatives used in anticancer therapies is mediated by human concentrative nucleoside transporters (hCNTs). hCNT1, the hCNT family member that specifically transports pyrimidines, is also a transceptor involved in tumor progression. In particular, oncogenesis appears to be associated with hCNT1 downregulation in some cancers, although the underlying mechanisms are largely unknown. Here, we sought to address changes in colorectal and pancreatic ductal adenocarcinoma-both of which are important digestive cancers-in the context of treatment with fluoropyrimidine derivatives. An analysis of cancer samples and matching non-tumoral adjacent tissues revealed downregulation of hCNT1 protein in both types of tumor. Further exploration of the putative regulation of hCNT1 by microRNAs (miRNAs), which are highly deregulated in these cancers, revealed a direct relationship between the oncomiRs miR-106a and miR-17 and the loss of hCNT1. Collectively, our findings provide the first demonstration that hCNT1 inhibition by these oncomiRs could contribute to chemoresistance to fluoropyrimidine-based treatments in colorectal and pancreatic cancer.

Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with limited therapeutic options. Curative therapy is limited to surgery whereas chemotherapy treatments are the election option for unresectable or metastatic cholangiocarcinoma. Cisplatin plus gemcitabine is the reference chemotherapy regimen, albeit the contribution to the median overall survival barely reaches one year. Drug transporters are undoubtedly a limiting step for drug bioavailability and have been clearly related to chemoresistance. Several members of the SoLute Carrier (SLC) superfamily involved in the uptake of anticancer drugs used to treat cholangiocarcinoma are downregulated in these tumors. This study shows the increase in the expression of specific drug transporters exerted by cisplatin treatment thereby enhancing their transport activity. Combination treatments of cisplatin with selected drugs as gemcitabine and sorafenib take in by these transporters at the desired combination schedule induced synergy. These data support the concept that proper administration pattern could favor treatment outcome.