Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.

In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.