Glaucarubulone glucoside from Castela macrophylla suppresses MCF‐7 breast cancer cell growth and attenuates benzo[a]pyrene‐mediated CYP1A gene induction

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 plan...

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Published in:Journal of applied toxicology 2017-07, Vol.37 (7), p.873-883
Main Authors: Badal, Simone A. M., Asuncion Valenzuela, Malyn M., Zylstra, Dain, Huang, George, Vendantam, Pallavi, Francis, Sheena, Quitugua, Ashley, Amis, Louisa H., Davis, Willie, Tzeng, Tzuen‐Rong J., Jacobs, Helen, Gangemi, David J., Raner, Greg, Rowland, Leah, Wooten, Jonathan, Campbell, Petreena, Brantley, Eileen, Delgoda, Rupika
Format: Article
Language:English
Subjects:
5-Fluorouracil
Adenocarcinoma
Anticancer properties
Antineoplastic Agents, Phytogenic - therapeutic use
Antioxidants
Antioxidants - therapeutic use
Antitumor agents
Apoptosis
Attenuation
Benzo(a)pyrene
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Cancer
Carcinogens
Cell death
Cell growth
Cell Line, Tumor - drug effects
Cell Proliferation - drug effects
chemoprevention
CYP1A protein
Cytochrome
Cytochrome P-450 Enzyme System - drug effects
Cytochrome P450
Cytotoxicity
Cytotoxins - therapeutic use
Endemic plants
Enzymes
Epithelial cells
Female
Gene expression
Gene Expression - drug effects
Genes
Glaucarubin - analogs & derivatives
Glaucarubin - therapeutic use
Humans
Hydrocarbons
Jamaica
Kinetics
Lymphocytes B
MCF-7 Cells - drug effects
Metabolites
natural product
Plant Extracts - therapeutic use
Polycyclic aromatic hydrocarbons
Pyrene
Quassinoids
Quassins - therapeutic use
Quinones
Reaction kinetics
Reactive oxygen species
Simaroubaceae - chemistry
Tamoxifen
Toxicity
Viability
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Summary: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. Glaucarubulone glucoside (Gg), isolated from the plant Castela macrophylla, reduced the viability of MCF‐7 breast adenocarcinoma cells (IC50 121 nm) to a greater extent than tamoxifen (IC50 >10 μm) and 4‐hydroxytamoxifen (IC50 2.6 μm) and did not impact non‐tumorigenic MCF‐10A cells. Gg induced apoptosis in MCF‐7 cells and downregulated the expression of antioxidant genes. Gg non‐competitively inhibited the activities of CYP1A enzymes and attenuated the ability of benzo[a]pyrene to induce CYP1A gene expression.
ISSN:0260-437X
1099-1263
DOI:10.1002/jat.3436