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. Graphic abstract

A Literature Curated Profile of miRNA IN Modulating Multi-Drug Resistance for Cancer Therapy

At present, cancer is one of the major causes of death, affecting millions of people each year. Multi Drug Resistance (MDR) remains the major clinical obstacle in cancer treatment. Till date various mechanisms of MDR has been elucidated which includes- over expression of drug transporter, defect in cell cycle and apoptotic machinery, induction of autophagy, alteration in drug metabolism and drug target. microRNAs (miRNAs) are an extensive class of 22 nucleotide long non coding RNAs which are involved in gene regulation. Recent work has underlined the involvement of miRNA in cancer development with several studies regarding their involvement in drug resistance, thereby holding much promise for developing novel and more effective therapy for cancer treatment. This review presents the mechanisms of MDR and focuses on the profile of miRNA in regulating MDR in cancer treatment. Keywords: miRNA, Cancer, Multi-drug resistance, Drug target, Drug transporter, Apoptotic machinery.

Use of photoimmunoconjugates to characterize ABCB1 in cancer cells

Accurate detection of ATP-binding cassette drug transporter ABCB1 expression is imperative for precise identification of drug-resistant tumors. Existing detection methods fail to provide the necessary molecular details regarding the functional state of the transporter. Photoimmunoconjugates are a unique class of antibody–dye conjugates for molecular diagnosis and therapeutic treatment. However, conjugating hydrophobic photosensitizers to hydrophilic antibodies is quite challenging. Here, we devise a photoimmunoconjugate that combines a clinically approved benzoporphyrin derivative (BPD) photosensitizer and the conformational-sensitive UIC2 monoclonal antibody to target functionally active human ABCB1 (i.e., ABCB1 in the inward-open conformation). We show that PEGylation of UIC2 enhances the BPD conjugation efficiency and reduces the amount of non-covalently conjugated BPD molecules by 17%. Size exclusion chromatography effectively separates the different molecular weight species found in the UIC2–BPD sample. The binding of UIC2–BPD to ABCB1 was demonstrated in lipidic nanodiscs and ABCB1-overexpressing triple negative breast cancer (TNBC) cells. UIC2–BPD was found to retain the conformation sensitivity of UIC2, as the addition of ABCB1 modulators increases the antibody reactivity in vitro. Thus, the inherent fluorescence capability of BPD can be used to label ABCB1-overexpressing TNBC cells using UIC2–BPD. Our findings provide insight into conjugation of hydrophobic photosensitizers to conformation-sensitive antibodies to target proteins expressed on the surface of cancer cells.