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Eur J Pharmacol. 2017 Nov 5;814:207-215. doi: 10.1016/j.ejphar.2017.08.025. Epub 2017 Aug 25.

Esculetin exerts antitumor effect on human gastric cancer cells through IGF-1/PI3K/Akt signaling pathway.

Author information

1
The First Affiliated Hospital, Jinzhou Medical University, Jinzhou 121001, China.
2
Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou 121001, China.
3
The Third Affiliated Hospital, Jinzhou Medical University; Jinzhou 121000, China. Electronic address: jyysyao@163.com.
4
The Third Affiliated Hospital, Jinzhou Medical University; Jinzhou 121000, China. Electronic address: 34159469@qq.com.

Abstract

In this study, we aimed to investigate the antitumor effect of esculetin, a coumarin derivative extracted from natural plants, on human gastric cancer cells, and to illustrate the potential mechanisms. The results showed that esculetin exhibited anti-proliferative effects against gastric cancer cells and induced their apoptosis in a dose dependent manner with lower toxicity against normal gastric epithelial cells. Mechanism study indicated that esculetin induced gastric cancer MGC-803 cells apoptosis by triggering the activation of mitochondrial apoptotic pathway through reducing the mitochondrial membrane potential (MMP), increasing Bax/Bcl-2 ratio, activating caspase-3 and caspase-9 activity, and increasing cytochrome c release from mitochondria. Further study showed that the pro-apoptotic effects of esculetin were associated with down-regulation of insulin-like growth factor-1/ phosphatidylinositide 3-kinase/protein kinase B (IGF-1/PI3K/Akt) signaling pathway. Activation of IGF-1/PI3K/Akt pathway by IGF-1 abrogated the pro-apoptotic effects of esculetin, while inhibition of IGF-1/PI3K/Akt pathway by triciribine or LY294002 enhanced the pro-apoptotic effects of esculetin. In addition, esculetin inhibited in vivo tumor growth with no obvious toxicity following subcutaneous inoculation of MGC-803 cells in nude mice, and inhibited activation of IGF-1/PI3K/Akt pathway in tumor tissue.

CONCLUSION:

These results indicate that esculetin could inhibit cell proliferation and induce apoptosis of gastric cancer cells through IGF-1/PI3K/Akt mediated mitochondrial apoptosis pathway, and may be a novel effective chemotherapeutic agent against gastric cancer.

KEYWORDS:

Apoptosis; Esculetin; Human gastric cancer cells; IGF-1; Mitochondria

PMID:
28847482
DOI:
10.1016/j.ejphar.2017.08.025
[Indexed for MEDLINE]

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