Anthricin Isolated fromAnthriscus sylvestris(L.) Hoffm. Inhibits the Growth of Breast Cancer Cells by Inhibiting Akt/mTOR Signaling, and Its Apoptotic Effects Are Enhanced by Autophagy Inhibition

Abstract

Anthricin (deoxypodophyllotoxin) is a natural product isolated from Anthriscus sylvestris (L.) Hoffm. (Apiaceae). Here, we investigated the effect of anthricin on autophagy and mammalian target of rapamycin (mTOR) signaling as anticancer actions in breast cancer cells. Many studies have supported the contention that the phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 pathway is considerably deregulated in breast cancer and that autophagy plays important roles in the development of this type of cancer, although the exact underlying mechanisms remain unknown. Our data confirmed that anthricin markedly induced apoptosis in 2 breast cancer cell lines, MCF7 (estrogen receptor positive) and MDA-MB-231 (estrogen receptor, progesterone receptor, and Her2/Neu receptor negative). Anthricin treatment decreased the levels of phosphorylated Akt and mTORC1, followed by inhibition of cell growth. Interestingly, blockage of autophagy by a pharmacological inhibitor or genetic deletion of ULK1 and Atg13 accelerated anthricin-induced apoptosis, suggesting that autophagy has cytoprotective effects. Taken together, our results indicate that anthricin is an inhibitor of mTOR and that a combination of an autophagy inhibitor and anthricin may serve as a new promising strategy for the treatment of breast cancer cells.

Ampelopsin‐induced autophagy protects breast cancer cells from apoptosis through Akt‐mTOR pathway via endoplasmic reticulum stress

“…Recent reports have suggested that the Akt‐mTOR signaling pathway is a major negative regulator of autophagy . The suppression of mTOR activity by rapamycin can induce autophagy and also reduce cell growth in different cancer cells . Now, we further determined whether the Akt‐mTOR pathway is involved in AMP‐induced autophagy.…”

“…Autophagy has often been observed as a consequence of ER stress and regarded as an alternate pathway to relieve ER stress or take part in cell death induced by ER stress . Activation of ER stress has recently been found in a variety of chemotherapeutic candidates' treatment in cancer cells along with induction of autophagy, although the mechanistic link between autophagy and ER stress remains not exactly clarified . Our previous study has shown that AMP could activate ER stress in both MCF‐7 and MDA‐MB‐231 cells, and PERK‐CHOP pathway plays a vital role in AMP‐induced cell apoptosis .…”

“…These results indicate that induction of autophagy is mediated by activation of ER stress induced by AMP in both breast cancer cells. Recent study has shown that Akt‐mTOR pathway is involved not only in ER stress‐induced apoptosis, but also in the induction of autophagy . In addition, ER stress has been reported to negatively regulate mTOR and thereby promote autophagy in cancer cells in response to chemotherapeutic agents .…”

“…Accumulating studies indicated that autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) kinase, and inhibition of the Akt‐mTOR pathway has been recently confirmed to lead cell growth inhibition along with activation of autophagy in cancer cells . Endoplasmic reticulum (ER) stress is considered to be an important regulator of several cellular pathological processes, including cancer cell death pathways in response to anticancer drugs .…”

The conditioned medium from osteo‐differentiating human mesenchymal stem cells affects the viability of triple negative MDA‐MB231 breast cancer cells

“…). In particular, in this cell line treatment with either bafilomycin A1, 3‐methyladenine or chloroquine, which are down‐regulators of autophagy, resulted in the potentiation of apoptosis induction following exposure to diverse compounds of natural origin such as plant‐derived anthricin, apigenin and sulforaphane …”