Abstract
Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion.
Highlights
Since estrogen is a key hormone that stimulates cancer growth during the initiation and promotion stages, regulating estrogen is important in the treatment of hormone-dependent breast cancer (Yager and Davidson, 2006)
The exposure concentrations (10-100 uM) of each flavonoid were chosen, considering cytotoxicity was not observed at a rate of more than 30% higher than the cells treated with the vehicle control (DMSO)
Aromatase inhibitory effects of flavonoids were reported, all experimental studies have focused on screening aromatase inhibitors using only single phytochemicals; mixture effects have not been investigated (Khan et al, 2011; Lu et al, 2012)
Summary
Since estrogen is a key hormone that stimulates cancer growth during the initiation and promotion stages, regulating estrogen is important in the treatment of hormone-dependent breast cancer (Yager and Davidson, 2006). Cytochrome P450 aromatase (CYP19) is the enzyme responsible for the key step in the biosynthesis of estrogen. It catalyzes the last step of estrogen biosynthesis, the aromatization of androgens to estrogen (Chumsri et al, 2011). It has been found in various extragonadal tissues such as the brain, liver, skin fibroblasts, and adipose tissues, as well as in the ovaries and testis, which are the gonadal tissues. Endocrine therapy using aromatase inhibitor can reduce the breast cancer risk, especially metastatic cancer (Behan et al, 2015; Iwase and Yamamoto, 2015; Mukhopadhyay et al, 2015)
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