Human equilibrative nucleoside transporter 1 and concentrative nucleoside transporter 1 in colorectal cancer: What do we know? A systematic review.

Colorectal cancer (CRC) remains a major global health challenge despite advances in screening, diagnosis, and treatment. This systematic review examines the roles of Human Equilibrative Nucleoside Transporter 1 (hENT1) and Human Concentrative Nucleoside Transporter 1 (hCNT1) in CRC, focusing on their expression, regulation, and impact on chemotherapeutic efficacy, particularly with nucleoside analogues like 5-fluorouracil (5-FU). We conducted a comprehensive literature search following PRISMA guidelines, yielding 29 studies that met our inclusion criteria. The review reveals variable expression of hENT1 and hCNT1 in CRC tissues compared with normal tissues, with implications for treatment response and development of resistance. Increased hENT1 expression is associated with poor outcomes and resistance to 5-FU, suggesting its potential as a biomarker for predicting treatment response. Conversely, hCNT1's role appears more complex, with its expression influencing the efficacy of other chemotherapeutic agents like gemcitabine and capecitabine. The review also highlights the lack of robust, standardised methods for assessing mRNA and protein levels, which complicates the interpretation of data and the establishment of these transporters as reliable clinical markers. Key findings include the potential therapeutic benefits of modulating hENT1 and hCNT1 expression to enhance drug efficacy and overcome resistance. The study underscores the need for further research using standardised and advanced methodologies, such as 3D cell culture assays, to better understand the mechanistic pathways and clinical implications of nucleoside transporter expression in CRC. Future research should aim to clarify the roles of hENT1 and hCNT1 in CRC and chemoresistance to develop targeted therapies and improve patient outcomes.