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World J Gastroenterol. Oct 28, 2021; 27(40): 6844-6860
Published online Oct 28, 2021. doi: 10.3748/wjg.v27.i40.6844
Role of human nucleoside transporters in pancreatic cancer and chemoresistance
Carly Jade Carter, Ahmed H Mekkawy, David L Morris
Carly Jade Carter, Ahmed H Mekkawy, David L Morris, Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, University of New South Wales, Sydney 2217, New South Wales, Australia
Carly Jade Carter, Ahmed H Mekkawy, David L Morris, Mucpharm Pty Ltd, Australia
Author contributions: Carter CJ wrote the manuscript and designed the figures with the support of Mekkawy AH; Mekkawy AH and Morris DL revised and supervised the manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: Morris DL is one of the inventors of BromAc and owns stocks in Mucpharm. Carter CJ and Mekkawy AH are employees of Mucpharm Pty Ltd.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: David L Morris, FRCS, FRCS (Ed), MBChB, MD, PhD, Professor, Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, University of New South Wales, Kogarah, Sydney 2217, New South Wales, Australia. david.morris@unsw.edu.au
Received: February 17, 2021
Peer-review started: February 17, 2021
First decision: April 5, 2021
Revised: April 19, 2021
Accepted: September 14, 2021
Article in press: September 14, 2021
Published online: October 28, 2021
Abstract

The prognosis of pancreatic cancer is poor with the overall 5-year survival rate of less than 5% changing minimally over the past decades and future projections predicting it developing into the second leading cause of cancer related mortality within the next decade. Investigations into the mechanisms of pancreatic cancer development, progression and acquired chemoresistance have been constant for the past few decades, thus resulting in the identification of human nucleoside transporters and factors affecting cytotoxic uptake via said transporters. This review summaries the aberrant expression and role of human nucleoside transports in pancreatic cancer, more specifically human equilibrative nucleoside transporter 1/2 (hENT1, hENT2), and human concentrative nucleoside transporter 1/3 (hCNT1, hCNT3), while briefly discussing the connection and importance between these nucleoside transporters and mucins that have also been identified as being aberrantly expressed in pancreatic cancer. The review also discusses the incidence, current diagnostic techniques as well as the current therapeutic treatments for pancreatic cancer. Furthermore, we address the importance of chemoresistance in nucleoside analogue drugs, in particular, gemcitabine and we discuss prospective therapeutic treatments and strategies for overcoming acquired chemoresistance in pancreatic cancer by the enhancement of human nucleoside transporters as well as the potential targeting of mucins using a combination of mucolytic compounds with cytotoxic agents.

Keywords: Pancreatic cancer, Gemcitabine, Human nucleoside transporters, Human equilibrative nucleoside transporters, Human concentrative nucleotide transporters, Mucins

Core Tip: Pancreatic cancer continues to be one of the leading causes of cancer-related mortality worldwide, with prevalence expected to increase drastically within the next decade primarily due to difficulties in diagnosis and acquired resistance to chemotherapeutic drugs. Due to this, in-depth work is extremely important for the future diagnosis and treatment of the disease. Human Nucleoside Transporters have been identified as a key target in not only diagnosis but also overcoming chemoresistance. Here, we summarize the information currently available on Pancreatic Cancer and the role of Nucleoside Transporters in chemoresistance.