Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells

Abstract

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.

Arctigenin prevents the progression of osteoarthritis by targeting PI3K/Akt/NF‐κB axis: In vitro and in vivo studies

“…Arctigenin, one component of dietary vegetables (greater burdock) in Asia, especially China, Korea and Japan, has therapeutic effect on anti‐influenza, antioxidant, antiviral, anti‐inflammatory, neuronal protection and anticancer treatment. However, no previous studies have clarified its effects and underlying mechanisms on the treatment of OA. Thus, the current study sheds new light on the potential protective role in OA both in vitro and in vivo.…”

“…Arctigenin (ATG), a phenylpropanoid dibenzylbutyrolactone lignan, is pulled from the seed of Arctium lappa L ( A lappa ), which is commonly known as greater burdock, a kind of edibles worldwide . More and more researchers have subscribed to the view that ATG possesses immeasurable pharmacological value, including antioxidant, neuronal protection, antiviral and anti‐inflammatory effects . The anti‐inflammatory effect has been confirmed on LPS‐induced inflammation models in RAW264.7 cells or human U937 macrophage cells by means of restraining NF‐κB, JAK‐STAT and MAPK pathway .…”

Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells

“…The anti-cancer activity of ATG has been reported to due to the induction of apoptosis mediated by mitochondrial disruption and cell cycle arrest in breast, lung, bladder, gastric, hepatic, and colon cancer cells [14][15][16][17][18]. In a recent study, we showed ATG suppressed metastatic potential and induced autophagic cell death by inhibiting estrogen receptor (ER) expression in MCF-7 human breast cancer cells [19,20]. Also, Wang et al reported human non-small cell lung cancer (NSCLC) cells treated with ATG exhibited greater chemosensitivity to cisplatin-induced apoptotic cell death mediated by the down-regulation of survivin [21].…”

3′‐Desmethylarctigenin induces G2/M cell cycle arrest and apoptosis through reactive oxygen species generation in hepatocarcinoma cells

“…Arctigenin exhibits distinct biological activities, including antiviral (Dias et al, ; Hayashi, Narutaki, Nagaoka, Hayashi, & Uesato, ), neuroprotection (Song et al, ; Zhu et al, ), antidiabetic (Huang et al, ; Zeng et al, ), and anticancer (Chen et al, ; Huang et al, ; Hsieh et al, ; Jeong, Hong, Jeong, & Koo, ; Lei, Gan, Zhao, Yu, & Hu, ; Li, Liang, Tian, & Hu, ; Maimaitili et al, ; Wang, Solorzano, et al, ; Susanti et al, ). A growing body of literature documents that arctigenin can induce cell cycle arrests, apoptosis, autophagy, and antimetastasis in multiple types of cancer cells, including prostate (Wang, Solorzano, et al, ), breast (Feng et al, ; Hsieh et al, ; Lou, Zhu, Zhao, Zhu, & Zhao, ; Maxwell, Lee, Kim, & Nam, ), lung (Lei et al, ), liver (Susanti et al, ), gastric (Jeong et al, ), ovarian (Huang et al, ), colon cancer (Li et al, ), and glioma (Maimaitili et al, ). The anticancer efficacy of arctigenin in vivo also has been reported in human cancer cell xenograft model in athymic nude mice (Feng et al, ; Wang, Solorzano, et al, ).…”