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Nicotinamide mononucleotide adenylyltransferase2 overexpression enhances colorectal cancer cell-kill by Tiazofurin
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Nicotinamide mononucleotide adenylyltransferase2 overexpression enhances colorectal cancer cell-kill by Tiazofurin
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Nicotinamide mononucleotide adenylyltransferase2 overexpression enhances colorectal cancer cell-kill by Tiazofurin
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Journal Article
Nicotinamide mononucleotide adenylyltransferase2 overexpression enhances colorectal cancer cell-kill by Tiazofurin
2013
Overview
Colorectal cancer cells exhibit limited cytotoxicity towards Tiazofurin, a pro-drug metabolized by cytosolic nicotinamide mononucleotide adenylyltransferase2 (NMNAT2) to thiazole-4-carboxamide adenine dinucleotide, a potent inhibitor of inosine 5′-monophosphate dehydrogenase required for cellular guanylate synthesis. We tested the hypothesis that colorectal cancer cells that exhibit low levels of NMNAT2 and are refractory to Tiazofurin can be rendered sensitive to Tiazofurin by overexpressing NMNAT2. Transfection of hNMNAT2 resulted in a six- and threefold cytoplasmic overexpression in Caco2 and HT29 cell lines correlating with Tiazofurin-induced enhanced cell-kill. Folate receptors expressed on the cell surface of 30–50% colorectal carcinomas were exploited for cellular targeting with Tiazofurin encapsulated in folate-tethered nanoparticles. Our results indicated that in wild-type colorectal cancer cells, free Tiazofurin-induced EC
50
cell-kill was 1500–2000 μ
M,
which was reduced to 66–156 μ
M
in hNMNAT2-overexpressed cells treated with Tiazofurin encapsulated in non-targeted nanoparticles. This efficacy was improved threefold by encapsulating Tiazofurin in folate-tethered nanoparticles to obtain an EC
50
cell-kill of 22–59 μ
M
, an equivalent of 100–300 mg m
−2
(one-tenth of the approved dose of Tiazofurin in humans), which will result in minimal toxicity leading to cancer cell-kill. This proof-of-principle study suggests that resistance of colorectal cancer cell-kill to Tiazofurin can be overcome by sequentially overexpressing hNMNAT2 and then facilitating the uptake of Tiazofurin by folate-tethered nanoparticles, which enter cells via folate receptors.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adenine
/ Antimetabolites, Antineoplastic - metabolism
/ Antimetabolites, Antineoplastic - pharmacology
/ Biomedical and Life Sciences
/ Cancer
/ Cell Survival - drug effects
/ Folic Acid Transporters - metabolism
/ Guanosine Triphosphate - metabolism
/ Humans
/ IMP Dehydrogenase - antagonists & inhibitors
/ Nicotinamide-Nucleotide Adenylyltransferase - genetics
/ Nicotinamide-Nucleotide Adenylyltransferase - metabolism
/ Ribavirin - analogs & derivatives
