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Introduction
Breast cancer has the highest incidence rate of all female malignancies (1). Breast cancer-related death ranks first among all cancer-related mortality in females (2). The prevention and treatment of breast cancer have received much attention in the field of oncology for years. Recently, there have been breakthroughs in the treatment of breast cancer, especially in endocrine therapy and molecular-targeted therapy (3-6). However, these therapies may only benefit certain patients; for triple-negative breast cancer or patients with a heavy tumor burden, the treatment choice is limited and the prognosis is still poor (7-9). Novel agents are urgently needed to enrich current treatment strategies. Following the success of artemisinin and paclitaxel, Traditional Chinese Medicine and natural plant extracts have received increasing attention in medical research (10,11), as they have important roles in the prevention and treatment of breast cancer (12).
Flavonoids are a class of small-molecule polyphenolic compounds and secondary metabolites of plants. Naturally occurring flavonoids are widely distributed in the roots, stems, and leaves of plants (13,14). Flavonoids perform various biological activities, including anti-inflammatory, antioxidant, anti-allergic and antiviral activities (15,16). Furthermore, flavonoids have effects in tumor prevention and treatment (17-19). Dietary intake of flavonoids has been negatively correlated with the risk incidence of a number of different types of cancer (20,21).
Fisetin, a natural flavonoid found in a variety of edible and medicinal plants, has been suggested to possess anti-tumor activity (13,22). Fisetin inhibits the proliferation, metastasis and invasiveness of lung cancer cells (23,24). A similar anti-tumor effect of fisetin has been observed in preclinical studies of colorectal cancer, prostate cancer, pancreatic cancer and melanoma (25-28), and it has been indicated that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) may be the target signaling pathway of fisetin (22). The PI3K/Akt/mTOR pathway is also known to have a central role in various cellular processes that contribute to the malignant phenotype of breast cancer (29-31). Previous studies have reported that fisetin and/or its nanoparticles induced cytotoxicity in MCF-7 and MDA-MB-231 cells by apoptosis in vitro (32-37), and another study reported the anti-tumor effect of fisetin in an MCF-7-bearing xenograft tumor model in vivo (38). However, the underlying mechanism of how fisetin induces apoptosis of breast cancer cells remains to be elucidated. Considering the...