title: Glaucarubulone glucoside from Castela macrophylla suppresses MCF-7 breast cancer cell growth and attenuates benzo[a]pyrene-mediated CYP1A gene induction.
abstract: Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside (Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF-7 breast adenocarcinoma cells (IC50= 121 nm) to a greater extent than standard of care anticancer agents 5-fluorouracil, tamoxifen (IC50>10 μm) and the tamoxifen metabolite 4-hydroxytamoxifen (IC50= 2.6 μm), yet was not cytotoxic to non-tumorigenic MCF-10A breast epithelial cells. Additionally, Gg induced MCF-7 breast cancer cell death. Gg blocked increases in reactive oxygen species in MCF-10A cells mediated by the polyaromatic hydrocarbon benzo[a]pyrene (B[a]P) metabolite B[a]P 1,6-quinone, yet downregulated the expression of genes that promote antioxidant activity in MCF-7 cells. This implies that Gg exhibits antioxidant and cytoprotective actions in non-tumorigenic breast epithelial cells and pro-oxidant, cytotoxic actions in breast cancer cells. Furthermore, Gg inhibited the activities of human CYP1A according to non-competitive kinetics and attenuated the ability of B[a]P to induce CYP1A gene expression in MCF-7 cells. These data indicate that Gg selectively suppresses MCF-7 breast cancer cell growth without impacting non-tumorigenic breast epithelial cells and blocks B[a]P-mediated CYP1A induction. Taken together, our data provide a rationale for further investigations of Gg and similar plant isolates as potential agents to treat and prevent breast cancer. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Natural Products Institute, Faculty of Science and Technology, University of the West Indies, Mona, Jamaica, West Indies.|Department of Basic Medical Sciences, Faculty of Medical Sciences, University of the West Indies, Mona, Jamaica, West Indies.
authors.forename: Simone A M
authors.initials: SAM
authors.lastname: Badal
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.
authors.forename: Malyn M
authors.initials: MM
authors.lastname: Asuncion Valenzuela
authors.affiliation: Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, 92350, USA.
authors.forename: Dain
authors.initials: D
authors.lastname: Zylstra
authors.affiliation: Department of Biological Sciences, Clemson University, Clemson, SC, 29634, USA.
authors.forename: George
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Vendantam
authors.affiliation: Natural Products Institute, Faculty of Science and Technology, University of the West Indies, Mona, Jamaica, West Indies.
authors.forename: Sheena
authors.initials: S
authors.lastname: Francis
authors.affiliation: Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, 92350, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Quitugua
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.
authors.forename: Louisa H
authors.initials: LH
authors.lastname: Amis
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.|Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, 92350, USA.
authors.forename: Willie
authors.initials: W
authors.lastname: Davis
authors.affiliation: Department of Biological Sciences, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Tzuen-Rong J
authors.initials: TJ
authors.lastname: Tzeng
authors.affiliation: Department of Chemistry, Faculty of Science and Technology, University of the West Indies, Mona, Jamaica, West Indies.
authors.forename: Helen
authors.initials: H
authors.lastname: Jacobs
authors.affiliation: Department of Biological Sciences, Clemson University, Clemson, SC, 29634, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gangemi
authors.affiliation: Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, 27402, USA.|Department of Biology and Chemistry, Liberty University, Lynchburg, VA, 24515, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Raner
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Rowland
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wooten
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.
authors.forename: Petreena
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Department of Basic Sciences, Center for Health Disparities and Molecular Medicine, Loma Linda University Health School of Medicine, Loma Linda, CA, 92350, USA.|Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, 92350, USA.|Department of Chemistry, University of California, Riverside, CA, 92521, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Brantley
authors.affiliation: Natural Products Institute, Faculty of Science and Technology, University of the West Indies, Mona, Jamaica, West Indies.
authors.forename: Rupika
authors.initials: R
authors.lastname: Delgoda
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D003603:Cytotoxins / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005900:Glaucarubin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007563:Jamaica; D061986:MCF-7 Cells / Q000187:drug effects; D010936:Plant Extracts / Q000627:therapeutic use*; D036702:Quassins / Q000627:therapeutic use; D029641:Simaroubaceae / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D003603:Cytotoxins; D010936:Plant Extracts; D036702:Quassins; C024967:glaucarubolone; D003577:Cytochrome P-450 Enzyme System; D005900:Glaucarubin
keywords: breast cancer; chemoprevention; cytochrome P450; cytotoxicity; natural product