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Abstract
Eupatorin has been reported with in vitro cytotoxic effect on several human cancer cells. However, reports on the mode of action and detail mechanism of eupatorin in vitro in breast cancer disease are limited. Hence, eupatorin’s effect on the human breast carcinoma cell line MCF-7 and MDA-MB-231 was investigated. MTT assay showed that eupatorin had cytotoxic effects on MCF-7 and MDA-MB-231 cells but was non-toxic to the normal cells of MCF-10a in a time-dose dependent manner. At 24 h, the eupatorin showed mild cytotoxicity on both MCF-7 and MDA-MB-231 cells with IC50 values higher than 20 μg/mL. After 48 h, eupatorin at 5 μg/mL inhibited the proliferation of MCF-7 and MDA-MB-231 cells by 50% while the IC50 of MCF-10a was significantly (p < 0.05) high with 30 μg/mL. The concentration of eupatorin at 5 μg/mL induced apoptosis mainly through intrinsic pathway by facilitating higher fold of caspase 9 compared to caspase 8 at 48 h. The cell cycle profile also showed that eupatorin (5 μg/mL) exerted anti-proliferation activity with the cell cycle arrest of MCF-7 and MDA-MB-231 cells at sub Gθ/G1 in a time-dependent manner. In addition, wound healing assay showed an incomplete wound closure of scratched MDA-MB-231 cells, and more than 60% of the MDA-MB-231 cells were prevented to migrate and invade the membrane in the Boyden chamber after 24 h. Eupatorin also inhibited angiogenic sprouting of new blood vessels in ex vivo mouse aorta ring assay. In gene expression assay, eupatorin up-regulated pro-apoptotic genes such as Bak1, HIF1A, Bax, Bad, cytochrome c and SMAC/Diablo and blocked the Phospho-Akt pathway. In conclusion, eupatorin is a potent candidate to induce apoptosis and concurrently inhibit the invasion, migration and angiogenesis of MDA-MB-231 and MCF-7 cells through inhibition of Phospho-Akt pathway and cell cycle blockade.
Highlights
Breast cancer is the most common form of cancer present in women worldwide and is the second leading cause of death after lung cancer[1,2]
The anti-proliferative effects of eupatorin were proposed as a result of CYP1 family enzyme metabolism[9]
CYP1A1, CYP1A2 and CYP1B1 are the members of human CYP1 family enzymes that participated in phase I metabolism of drugs in the liver[17,18]
Summary
Breast cancer is the most common form of cancer present in women worldwide and is the second leading cause of death after lung cancer[1,2]. Eupatorin (3′,5-dihydroxy-4′,6,7-trimethoxyflavone) is one of the potent candidates as anti-breast cancer agents[9,10]. This bioactive compound belongs to the flavone group, commonly found in a variety of fruits, vegetables, and herbs[6]. The MCF-7 cell model has been examined extensively to determine the mechanism of estrogen-stimulated growth in tumour[13]. MDA-MB-231 (estrogen-receptor negative) cells that are aggressive and invasive triple negative breast cancer (TNBC) cells are known to be resistant to several anti-cancer agents[14]. This study was aimed to evaluate the cytotoxic effect and apoptosis induction of eupatorin in MCF-7 and MDA-MB-231 cells line in vitro. By comparing breast cancer cell lines (MCF-7 and MDA-MB-231) with MCF-10a, the selectivity of eupatorin cytotoxic effects on cancer cells was determined
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