Department of Pharmacology, School of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju 38066, Republic of Korea.
Int J Oncol. 2018 Apr;52(4):1339-1349. doi: 10.3892/ijo.2018.4271. Epub 2018 Feb 9.
Arctigenin, a member of the Asteraceae family, is a biologically active lignan that is consumed worldwide due to its several health benefits. However, its use may pose a problem for patients with estrogen receptor (ER)α-positive breast cancer, since studies have shown that arctigenin is a phytoestrogen that exerts a proliferative effect by binding to the ER. Thus, in this study, we examined the effect of arctigenin on ERα-positive MCF-7 human breast cancer cells to determine whether the consumption of arctigenin is safe for patients with breast cancer. First, we found that arctigenin inhibited the viability of the MCF-7 cells, and colony formation assay confirmed that this effect was cytotoxic rather than cytostatic. The cytotoxic effects were not mediated by cell cycle arrest, apoptosis, or necroptosis, despite DNA damage, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylated H2A.X. An increase in lipidated LC3, a marker of autophagosome formation, was observed, indicating that autophagy was induced by arctigenin, which was found to be triggered by the inhibition of the mechanistic target of rapamycin (mTOR) pathway. We then examined the effects of arctigenin on ERα expression and determined whether it affects the sensitivity of the cells to tamoxifen, as tamoxifen is commonly used against hormone-responsive cancers and is known to act via the ERα. We found that treatment with arctigenin effectively downregulated ERα expression, which was found to be a consequence of the inhibition of the mTOR pathway. However, treatment with arctigenin in combination with tamoxifen did not affect the sensitivity of the cells to tamoxifen, but instead, exerted a synergistic effect. On the whole, our data indicate that the phytoestrogen, arctigenin, mainly targeted the mTOR pathway in ERα-positive MCF-7 human breast cancer cells, leading to autophagy-induced cell death and the downregulation of ERα expression. Furthermore, the synergistic effects between arctigenin and tamoxifen suggest that the consumption of arctigenin is not only safe for patients with hormone-sensitive cancers, but may also be an effective co-treatment.
牛蒡子苷元，来自菊科植物，是一种具有生物活性的木脂素，由于其多种健康益处，在全球范围内被消费。然而，对于雌激素受体 (ER)α 阳性乳腺癌患者来说，它的使用可能会带来问题，因为研究表明牛蒡子苷元是一种植物雌激素，通过与 ER 结合发挥增殖作用。因此，在这项研究中，我们研究了牛蒡子苷元对 ERα 阳性 MCF-7 人乳腺癌细胞的影响，以确定牛蒡子苷元的消费是否对乳腺癌患者安全。首先，我们发现牛蒡子苷元抑制 MCF-7 细胞的活力，集落形成实验证实这种作用是细胞毒性而不是细胞静止。尽管存在 DNA 损伤，如多聚（ADP-核糖）聚合酶 (PARP) 裂解和磷酸化 H2A.X，但细胞周期停滞、凋亡或坏死都不是细胞毒性的介导因素。观察到脂质化 LC3 的增加，这是自噬体形成的标志物，表明自噬被牛蒡子苷元诱导，而自噬被发现是由机械靶标雷帕霉素 (mTOR) 途径的抑制引发的。然后，我们检查了牛蒡子苷元对 ERα 表达的影响，并确定它是否影响细胞对他莫昔芬的敏感性，因为他莫昔芬通常用于治疗激素反应性癌症，并且已知通过 ERα 起作用。我们发现，用牛蒡子苷元处理可有效下调 ERα 的表达，这是 mTOR 途径抑制的结果。然而，用牛蒡子苷元和他莫昔芬联合处理不会影响细胞对他莫昔芬的敏感性，反而会产生协同作用。总的来说，我们的数据表明，植物雌激素牛蒡子苷元主要靶向 ERα 阳性 MCF-7 人乳腺癌细胞中的 mTOR 途径，导致自噬诱导的细胞死亡和 ERα 表达的下调。此外，牛蒡子苷元和他莫昔芬之间的协同作用表明，牛蒡子苷元的消费不仅对激素敏感的癌症患者安全，而且可能是一种有效的联合治疗方法。
