Abstract
Ampelopsin (AMP), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. In this study, we investigated its anti-cancer activity in human breast cancer cell lines, and explored the underlying mechanism of this action. Our results showed that treatment with AMP dose-dependently inhibited cell viability and induced apoptosis in MCF-7 and MDA-MB-231 breast cancer cells without cytotoxicity in human normal breast epithelial cells MCF-10A. Meanwhile, AMP dose- dependently triggered reactive oxygen species (ROS) generation in both breast cancer cells. The ROS scavenger N-acetyl-L-cysteine (NAC) strongly attenuated AMP-induced ROS production, along with cell growth inhibition and apoptosis. Furthermore, AMP was observed to activate endoplasmic reticulum (ER) stress, as evidenced by the up-regulation of ER stress-related proteins, including GRP78, p-PERK, p-elF2α, cleaved ATF6α and CHOP, while knockdown of ATF6α or PERK markedly down-regulated AMP-induced CHOP expression. Blocking ER stress using 4-phenylbutyric acid not only down-regulated AMP-induced GRP78 and CHOP expression, but also significantly decreased AMP-induced cell growth inhibition and apoptosis, whereas ER stress inducer thapsigargin played opposing effects. Additionally, NAC inhibited AMP-induced ER stress by down-regulating GRP78 and CHOP expression. Conversely, blocking ER stress using CHOP siRNA decreased AMP-induced ROS production and cell apoptosis. Taken together, these results demonstrate that AMP has anti-tumor effects against breast cancer cells through ROS generation and ER stress pathway, which therefore provide experimental evidences for developing AMP as a new therapeutic drug for breast cancer.
Highlights
Significant progress has been achieved in the development of targeted therapies, breast cancer as the most common cancer develops to be the leading cause of cancer-related deaths in women [1,2]
AMP induces cell growth inhibition and apoptosis in human breast cancer cells To investigate whether AMP has an anti-tumor role in breast cancer, the Cell Counting Kit-8 (CCK-8) assay was adopted to evaluate the cytotoxic effects of AMP on estrogen receptor- positive and negative breast cancer cells lines MCF-7 and MDA-MB-231, as well as human normal breast epithelial cells MCF-10A, respectively
Our studies demonstrate that AMP can induce growth inhibition of breast cancer cells, and its growth inhibitory effect is independent of estrogen receptor status
Summary
Significant progress has been achieved in the development of targeted therapies, breast cancer as the most common cancer develops to be the leading cause of cancer-related deaths in women [1,2]. New therapeutic strategy and chemotherapeutic candidates for breast cancer are urgently needed to explore[3]. Natural products are major resources of prospective anti-cancer candidates [4,5], for example paclitaxel, commonly used in breast cancer treatment, is isolated from the bark of the Pacific yew tree [6,7]. Ampelopsin (AMP), named dihydromyricetin, one of flavonoids, is the major bioactive constituent of Ampelopsis grossedentata [8,9,10]. It has been reported that AMP exerts a number of biological and pharmacological actions including hypoglycemic, anti-oxidative, and hepato-protective effects [11,12]. Its anti-tumor effects on breast cancer have not been explored and its underlying mechanism of action remains to be elucidated
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