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Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study.
Int J Mol Sci. 2021 Feb 05; 22(4)IJ

Abstract

Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer's disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu-kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer's disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders.

Authors+Show Affiliations

Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37 Bratislava, Slovakia.Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37 Bratislava, Slovakia.Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia.Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia.Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia.Zoology Department, College of Science, King Saud University, Riyadh 12372, Saudi Arabia.Zoology Department, College of Science, King Saud University, Riyadh 12372, Saudi Arabia.Fresh-Lands Environmental Actions, Reading, Berkshire RG4 5BE, UK.Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37 Bratislava, Slovakia. Zoology Department, College of Science, King Saud University, Riyadh 12372, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33562744

Citation

Simunkova, Miriama, et al. "Antioxidant Vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: a ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study." International Journal of Molecular Sciences, vol. 22, no. 4, 2021.
Simunkova M, Barbierikova Z, Jomova K, et al. Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study. Int J Mol Sci. 2021;22(4).
Simunkova, M., Barbierikova, Z., Jomova, K., Hudecova, L., Lauro, P., Alwasel, S. H., Alhazza, I., Rhodes, C. J., & Valko, M. (2021). Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study. International Journal of Molecular Sciences, 22(4). https://doi.org/10.3390/ijms22041619
Simunkova M, et al. Antioxidant Vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: a ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study. Int J Mol Sci. 2021 Feb 5;22(4) PubMed PMID: 33562744.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antioxidant vs. Prooxidant Properties of the Flavonoid, Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity, Fenton Reaction and DNA Damage Study. AU - Simunkova,Miriama, AU - Barbierikova,Zuzana, AU - Jomova,Klaudia, AU - Hudecova,Lenka, AU - Lauro,Peter, AU - Alwasel,Saleh H, AU - Alhazza,Ibrahim, AU - Rhodes,Christopher J, AU - Valko,Marian, Y1 - 2021/02/05/ PY - 2021/01/04/received PY - 2021/01/29/revised PY - 2021/02/03/accepted PY - 2021/2/10/entrez PY - 2021/2/11/pubmed PY - 2021/9/3/medline KW - antioxidant KW - copper KW - flavonoid KW - gel-electrophoresis KW - kaempferol KW - prooxidant KW - spectroscopy KW - viscometry JF - International journal of molecular sciences JO - Int J Mol Sci VL - 22 IS - 4 N2 - Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer's disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu-kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer's disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/33562744/Antioxidant_vs__Prooxidant_Properties_of_the_Flavonoid_Kaempferol_in_the_Presence_of_Cu_II__Ions:_A_ROS_Scavenging_Activity_Fenton_Reaction_and_DNA_Damage_Study_ L2 - https://www.mdpi.com/resolver?pii=ijms22041619 DB - PRIME DP - Unbound Medicine ER -