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.
Highlights
Estrogen signaling is crucial for breast cancer initiation and progression
More than 20% of patients suffer from recurrence at a certain point of their lives
Most breast tumors (~ 80%) highly express estrogen receptor (ER) promoting cancer cell proliferation. These estrogendependent tumors are affected by numerous genetic and physiological factors upon which different risk groups are identified where high-risk ones are recommended to be placed on a prophylactic regimen of ER modulators at their menopause to decrease the risk/chances of developing the d isease[34]
Summary
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. 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. The conventional treatment for hormone-responsive breast cancer, involves the use of selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs) and aromatase inhibitors. Aromatase inhibitors prevent extragonadal estrogen biosynthesis playing an important role in the management of estrogen-dependent breast cancer, in postmenopausal women[8]. Synthetic aromatase inhibitors such as letrozole and anastrozole have been used as supportive treatments for postmenopausal breast cancer p atients[9,10]
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