Role of human nucleoside transporters in pancreatic cancer and chemoresistance

Table 1 The current chemotherapeutic and chemoprotectant agents used to treat pancreatic cancer, their classification, action, and chemical structure

Drug	Classification	Action
Gemcitabine (Gemzar)	Antimetabolite	Pyrimidine antagonist
Doxorubicin (Rubex)	Anthracycline Antibiotic	Cell-cycle specific antagonist
Fluorouracil (5-FU)	Antimetabolite	Pyrimidine antagonist
Paclitaxel (Abraxane)	Plant alkaloid, Taxane, Antimircotubule	Inhibition of cell microtubule structures
Oxaliplatin (Eloxatin)	Alkylating agent	Cell-cycle non-specific antagonist
Leucovorin (Folinic acid)	Chemoprotectant	Enhancement anti-cancer effects
Irinotecan (Camptosar)	Plant alkaloid, Topoisomerase I inhibitor	Camptothecan analogs
Erlotinib (Tarceva)	Tyrosine kinase inhibitor	Ant-EGFR
Cetuximab (Erbitux)	Biologic	Anti-EGFR
Bevacizumab (Avastin)	Biologic	Anti-VEGF

Citation: National Center for Biotechnology Information, 2021 [cited 12 April 2021]. Database: PubChem Compound Summary [Internet]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Gemcitabine[70,71].

Table 2 The mechanisms, efficacy, toxicity, affinity, and disadvantages of human nucleoside transporters

Transporter	Mechanisms of action	Efficacy, toxicity, and affinity	Known disadvantages	Ref.
hENT1 (SLC29A1)	Nucleoside-derived anticancer drug update. Antiviral drug uptake. Cellular uptake of nucleosides for RNA or DNA synthesis. Adenosine signalling	Clear correlation between the efficacy of nucleoside analog chemotherapeutic treatment and expression of hENT1. Increase in chemotherapeutic drug efficacy with an increase in transporter expression. Highly sensitive to NBMPR, draflazine, dilazep, and dipyridamole.Increase in cell toxicity with an increase in transporter expression. Highest affinity for gemcitabine uptake	Mutations in the SLC29A1 gene associated with Faisalabad histiocytosis, pigmented hypertrichosis including insulin dependent diabetes, and H syndrome. Select variants of the gene highly immunogenic, may result in haemolytic disease of newborns and foetus as well as acute haemolytic transfusion reaction	[72-77]
hENT2 (SLC29A2)	Nucleoside-derived anticancer drug update. Antiviral drug uptake Mediates the influx and efflux of pyrimidine and purine nucleosides as well as the purine base hypoxanthine. Transport’s bile salts, metal ions, organic acids, amine compounds, glucose and other sugars	Although identified to transport gemcitabine into cells, it is less effective than hENT1 at cytotoxic drug uptake. Minimally sensitive to inhibition via NBMPR, draflazine, dilazep, and dipyridamole. Higher affinity for nucleobases when compared to hENT1	Mutations in the SLC29A2 gene associated with familial and Histiocytosis-Lymphadenopathy Plus Syndrome and hepatic Adenomas. Dysregulation may result in have adverse effects on cell homeostasis and possibly contribute to tumour progression	[33,37,38,40,78]
hCNT1 (SLC28A1)	Transport’s bile salts, metal ions, organic acids, amine compounds, glucose and other sugars. Transport’s nucleosides, related molecules, and vitamins. Nucleoside binding. Nucleoside sodium symporter activity. Nucleoside-derived anticancer drug update. Antiviral pyrimidine nucleoside analog drug uptake	Minimally effective at cytotoxic drug uptake. Expression is negatively regulated by MUC4 in gemcitabine resistant pancreatic cancer cells. Has a selective inhibition for thymidine, adenosine, uridine, inosine, guanosine, and cytidine	Mutations in the SLC28A1 gene are associated with Uridine-Cytidineuria disease. Overexpression of protein may result in translocation of pyrimidine alone, resulting in modifications of cell physiology	[16,45,51,79]
hCNT3 (SLC28A3)	Regulates cellular processes, such as vascular tone, neurotransmission, surface receptors, the concentration of adenosine in the vicinity of cell as well as transport, and finally the metabolism of nucleoside drugs. hCNT3 has a broad specificity for pyrimidine and purine nucleosides	Clear correlation between hCNT3 downregulation and gemcitabine toxicity	Mutations in the SLC28A3 gene results in the altered sensitivity to the compound BMS-536924	[80-82]

hENT1/2: Human equilibrative nucleoside transporter 1/2; hCNT1/3: Human concentrative nucleoside transporter 1/3.