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Dictamnine Promotes Apoptosis and Inhibits Epithelial-Mesenchymal Transition, Migration, Invasion and Proliferation by Downregulating the HIF-1α and Slug Signaling Pathways

Dictamnine Promotes Apoptosis and Inhibits Epithelial-Mesenchymal Transition, Migration, Invasion and Proliferation by Downregulating the HIF-1α and Slug Signaling Pathways

Jing Ying Wang, Zhe Wang, Ming Yue Li, Zhihong Zhang, Chunliu Mi, Hong Xiang Zuo, Yue Xing, Yan-Ling Wu, Li-Hua Lian, Guang Hua Xu, Lian Xun Piao, Juan Ma, Xuejun Jin

Chem Biol Interact. 2018 Dec 25;296:134-144.

PMID: 30266538

Abstract:

Dictamnine (DTM) is a natural alkaloid isolated from the root of Dictamnus dasycarpus Turcz and has been shown to exhibit multiple biological functions, including anti-inflammatory, antifungal, anti-angiogenic and anticancer activity. However, the mechanisms by which dictamnine inhibits tumor growth are not fully understood. In this study, we investigated the effectiveness of dictamnine as a treatment for cancer and to identify the underlying mechanisms of its anticancer activity. Here, dictamnine showed the potent inhibitory activity against HIF-1α and Slug activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α and Slug protein in a dose-dependent manner. Further analysis revealed that dictamnine inhibited HIF-1α protein synthesis, without affecting its degradation. Our results demonstrated that dictamnine reduced HIF-1α protein synthesis by downregulating the mTOR/p70S6K/eIF4E and MAPK pathways, and reduced the expression of Slug by inhibiting the GSK-3β/Slug signaling pathway. Moreover, epithelial-mesenchymal transition (EMT) was inhibited in dictamnine-treated tumors by downregulation of HIF-1α and Slug, as reflected by the upregulation of E-cadherin and Occludin, and the downregulation of N-cadherin and Vimentin. Phenomenological experiments showed that dictamnine reduced migration and invasion, inhibited HCT116 cell proliferation and promoted HCT116 cell apoptosis by downregulating HIF-1α and Slug. In vivo studies further confirmed that dictamnine treatment caused significant inhibition of tumor growth in a xenograft tumor model. These findings suggest that dictamnine is a potent cancer inhibitor, providing a rationale for anticancer pathway-targeted therapy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP484297	Dictamnine		484-29-7	Price

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