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作者

Xiao-shan Hao Pan-pan Feng Yun-yun Zhang Feng-ze Wang Gui-ling Wang Hong-rong Fei

作者单位

²These authors contributed equally to this work. ¹School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, PR China ³School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, PR China

刊名

Chemico-Biological Interactions

年份

2023

卷号

Vol.378

页码

110487

ISSN

0009-2797

关键词

DNA damage EGFR ER stress MAPK ROS Scutebarbatine A.

摘要

Scutebarbatine A , a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2′-deoxyuridine incorporation and colony formation assay. DNA double-strand breaks were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was ass...更多

Scutebarbatine A , a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2′-deoxyuridine incorporation and colony formation assay. DNA double-strand breaks were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was assessed by flow cytometry. Apoptosis was determined by a TUNEL assay. Intracellular reactive oxygen species generation and superoxide production were measured with 2′, 7′-dichlorofluorescein diacetate and dihydroethidium staining, respectively. The results indicated that SBT-A showed a dose-dependent cytotoxic effect against breast cancer cells while revealing less toxicity toward MCF-10A breast epithelial cells. Moreover, SBT-A remarkably induced DNA damage, cell cycle arrest and apoptosis in both MDA-MB-231 and MCF-7 cells. SBT-A treatment increased the levels of ROS and cytosolic superoxide production. Pretreatment with N-acetyl cysteine , a ROS scavenger, was sufficient to block viability reduction, DNA damage, apoptosis and endoplasmic reticulum stress caused by SBT-A. By exposure to SBT-A, the phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase was upregulated, while the phosphorylation of extracellular signal-regulated kinase was downregulated. In addition, SBT-A inhibited the EGFR signaling pathway by decreasing EGFR expression and phosphorylation of Akt and p70S6K. As mentioned above, SBT-A has a potent inhibitory effect on breast cancer cells through induction of DNA damage, apoptosis and ER stress via ROS generation and modulation of MAPK and EGFR/Akt signaling pathway.收起

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