title: Application of artificial neural network to investigate the effects of 5-fluorouracil on ribonucleotides and deoxyribonucleotides in HepG2 cells.
abstract: Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: QianQian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Christopher Wai Kei
authors.initials: CW
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Caiyun
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Vincent Kam Wai
authors.initials: VK
authors.lastname: Wong
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Fengguo
authors.initials: F
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: ZhiHong
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D003597:Cytosine Nucleotides / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D006150:Guanine Nucleotides; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008954:Models, Biological; D016571:Neural Networks, Computer; D012265:Ribonucleotides / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D013942:Thymine Nucleotides / Q000378:metabolism; D014500:Uracil Nucleotides / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D003597:Cytosine Nucleotides; D003854:Deoxyribonucleotides; D006150:Guanine Nucleotides; D012265:Ribonucleotides; D013942:Thymine Nucleotides; D014500:Uracil Nucleotides; D005472:Fluorouracil