Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer

Abstract

Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC50s and were therefore selected for further assays. In silico molecular modeling against ER and aromatase was performed for the three compounds. In vivo estrogenic and anti-estrogenic assays confirmed an anti-estrogenic activity for the isolates. Moreover, naringenin, naringin and quercetin demonstrated in vitro inhibitory potential against aromatase enzyme along with anticancer potential in vivo, as evidenced by decreased tumor volumes. Reduction in aromatase levels in solid tumors was also observed in treated groups. Overall, this study suggests an antitumor potential for naringenin, naringin and quercetin isolated from citrus peels in breast cancer via possible modulation of estrogen signaling and aromatase inhibition suggesting their use in pre- and post-menopausal breast cancer patients, respectively.

Aqueous Extract of Dacryodes edulis (Burseraceae) Leaves Inhibited Tumor Growth in Female Wistar Rats with 7,12-Dimethylbenz[a]anthracene-Induced Breast Cancer

“…ese effects could be attributed to the presence of flavonoids and flavonols (phytoestrogens) in the aqueous extract of D. edulis leaves [4]. e so-called phytoestrogens were reported to be able to compete with endogenous estrogens for binding estrogen receptors and to inhibit aromatase activity [51]. As recently suggested by Gul et al [44], phytoestrogenic molecules are capable of inhibiting estrogen activity (antagonistic effect against ER) or estrogen synthesis (inhibition of aromatase synthesis).…”

Bioactive Compounds of Citrus Fruits: A Review of Composition and Health Benefits of Carotenoids, Flavonoids, Limonoids, and Terpenes

“…A significant amount of research has been conducted to recover the commercially vital compounds from citrus fruit pomace [ 60 , 61 , 62 ]. Citrus peel is a rich source of essential oils [ 63 ], carotenoids [ 64 , 65 , 66 ], pectin [ 67 , 68 ], flavonoids [ 69 , 70 , 71 ], and several other bioactive components with excellent antioxidant [ 69 ] and health-promoting potential [ 62 , 72 , 73 , 74 ]. Among the flavonoids, hesperidin, naringin, rutin, and neohesperidin are the major flavonoids found in the peel of citrus fruits [ 71 , 74 ], with especially high amounts in mandarins, which exhibit high antioxidant potency [ 71 ].…”

Protective Effects of Naringenin from Citrus sinensis (var. Valencia) Peels against CCl4-Induced Hepatic and Renal Injuries in Rats Assessed by Metabolomics, Histological and Biochemical Analyses

“…Several hydroxylated or methoxylated flavonoids have been reported from different Citrus peels, with potential biological activities, such as free radical scavenging and antiaromatase, antiestrogenic and anti-inflammation activities [9,12]. Naringenin is one of the main flavonoids of the different extracts of edible fruits and peels of the Citrus family [9]. It is a flavanone with significant biological and pharmaceutical effects, such as antitumor, anti-inflammatory antioxidant, antiatherogenic, antidepressant and antidiabetic effects [13] Metabolomics analysis is a modern tool used in drug development, disease diagnosis and prognosis that offers a greater level of biochemical depth and knowledge than other systems biology omics techniques [14].…”