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

作者：Badal Simone A M; Valenzuela Malyn M Asuncion; Zylstrac 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

来源：Journal of Applied Toxicology, 2017, 37(7): 873-883.

DOI：10.1002/jat.3436

• chemoprevention
• natural product
• cytotoxicity
• breast cancer
• cytochrome P450

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 mu M) and the tamoxifen metabolite 4-hydroxytamoxifen (IC50 = 2.6 mu M), 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.

• 出版日期2017-7