title: Effects of pharmacological ascorbate on hemoglobin-induced cancer cell proliferation.
abstract: The high heme content in red meat is associated with an increased risk of developing cancer. Pharmacologic concentrations of ascorbate can specifically kill a wide range of cancer cells. In this study, the impact of ascorbate at pharmacologic concentrations on hemoglobin (Hb)-modulated human hepatoma HepG2 cell survival was investigated. It was found that HepG2 cells were proliferated by Hb (5-25μM), but killed by high pharmacologic concentrations of ascorbate (2-10mM). Although ascorbate at the low pharmacologic concentration (0.5mM) alone exhibited insignificant effect on cell viability, it effectively inhibited Hb (10μM)-induced cancer cell proliferation. The mechanism of this cytotoxicity was based on the production of extracellular H2O2and involved transition iron. The influence of ascorbate on Hb-dependent redox reactions (i.e. the oxidative stability of Hb and its cytotoxic ferryl intermediate) was further investigated to illustrate the reaction mechanism of ascorbate toxicity, where H2O2was generated in the reaction of ascorbate with Hb. Furthermore, circular dichroism demonstrated no significant change in the secondary structure of Hb after ascorbate addition and molecular docking revealed binding modes of ascorbate with Hb. These results demonstrated that ascorbate could possess anti-cancer activity through interfering in Hb-dependent redox reactions.
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China. Electronic address: naihaolu@jxnu.edu.cn.
authors.forename: Naihao
authors.initials: N
authors.lastname: Lu
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Physics, University of Houston, Houston, TX, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Physics, University of Houston, Houston, TX, USA.
authors.forename: Jianfa
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China. Electronic address: yiyuanpeng@yahoo.com.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Peng
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006418:Heme / Q000737:chemistry; D006454:Hemoglobins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D006454:Hemoglobins; D006418:Heme; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid
keywords: Ascorbate; Cancer cells; Hemoglobin