title: High glucose modulates antiproliferative effect and cytotoxicity of 5-fluorouracil in human colon cancer cells.
abstract: 5-Fluorouracil (5-FU)-based chemotherapy is widely used for the treatment of colorectal cancer (CRC). While optimal doses of 5-FU are generally established based on a patient's estimated body surface area, the plasma concentrations of 5-FU vary among patients. In addition, hyperglycemia in patients with CRC has been reported as a risk factor in poor prognosis. The aim of the present study was to investigate whether hyperglycemia affects antiproliferative effect of 5-FU on the human colon cancer cells (SW480, SW620, LoVo, and HCT116). Growth inhibition of 5-FU was accessed by WST-8 assay. The effect of high glucose (HG, 15 mM) and 5-FU on the cellular proliferation was evaluated by flow cytometry analysis using 5-ethynyl-2'-deoxy-uridine (EdU) incorporation plus 7-AAD. Cell death was determined by flow cytometry using Annexin V-FITC and PI. The results showed that HG, compared to physiological normal glucose (NG) concentration (5 mM), leads to increased cell proliferation and increased GI50 of 5-FU in the four colon cancer cell lines. When the cells were pretreated with a low-dose 5-FU in NG condition, subsequent HG treatment eliminated inhibitory effect of 5-FU in cancer cell growth. In the presence of 5-FU (0.5 μg/mL for LoVo and HCT116; 1 μg/mL for SW480 and SW620), culture with HG for 72 h does not significantly altered cell cycle profile in the four cell lines but significantly increased DNA replication in SW620 (21%) and LoVo (17%). Flow cytometric analysis showed that HG protects cells against 5-FU-induced cell death in SW480. Finally, HG did not alter intracellular level of reactive oxygen species (ROS), although 5-FU indeed induced higher intracellular level of ROS. In conclusion, HG attenuates growth inhibition of 5-FU and our results indicate that decreased cell death and increased DNA replication may account for the attenuating effect of a HG environment on 5-FU-induced tumor growth inhibition.
authors.affiliation: 1 Graduate Institute of Genome Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung, Taiwan .
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Ma
authors.forename: I-Ping
authors.initials: IP
authors.lastname: Yang
authors.forename: Hsiang-Lin
authors.initials: HL
authors.lastname: Tsai
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Huang
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy*; D004261:DNA Replication / Q000187:drug effects; D003856:Deoxyuracil Nucleotides; D005434:Flow Cytometry; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D013778:Tetrazolium Salts
chemical_list: C476329:2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt; D003856:Deoxyuracil Nucleotides; D013778:Tetrazolium Salts; C027383:2'-deoxy-5-ethyl-5'-uridylic acid; D005947:Glucose; D005472:Fluorouracil