title: Assessing dose-dependent differences in DNA-damage, p53 response and genotoxicity for quercetin and curcumin.
abstract: As part of a longer-term goal to create a quantitative mechanistic model of the p53-Mdm2 DNA-damage pathway, we are studying cellular responses to compounds causing DNA-damage by various modes-of action, including two natural polyphenols: quercetin (QUE) and curcumin (CUR). QUE and CUR are weak mutagens in some in vitro assays and possess both anti- or pro-oxidant effects depending on dose. This study examines the dose-response of DNA-damage pathway to these compounds in HT1080 cells (a human cell line with wild-type p53) at doses relevant to human exposure. CUR was more potent in causing reactive oxygen species, DNA damage (measured as phospho-H2AX) and p53 induction, with lowest observed effect levels (LOELs; 3-8 μM) approximately three-fold lower than QUE (20-30 μM). CUR showed a strong G2/M arrest and apoptosis at ≈ 10 μM. QUE caused S phase arrest at low doses (8 μM) and apoptosis was only induced at much higher doses (60 μM). At concentrations with similar levels of p-H2AX and p53 biomarkers, CUR caused greater micronuclei frequency. CUR induced clear increases micronuclei at 3-6 μM, while QUE had a weaker micronuclei response even at the highest doses. Thus, even with two compounds sharing common chemistries, DNA-damage response patterns differed significantly in terms of dose and cell fate.
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ross
authors.forename: O Joseph
authors.initials: OJ
authors.lastname: Trask
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.forename: Matthew
authors.initials: M
authors.lastname: Dent
authors.forename: Andrew
authors.initials: A
authors.lastname: White
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Clewell
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003474:Curcumin / Q000633:toxicity*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009153:Mutagens / Q000633:toxicity*; D009336:Necrosis / Q000139:chemically induced; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011794:Quercetin / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens; D016877:Oxidants; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011794:Quercetin; D003474:Curcumin
keywords: Curcumin; DNA damage; DNA repair; Micronucleus; Polyphenols; Quercetin; p53