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Expert Opin Ther Targets. 2016;20(1):7-18. doi: 10.1517/14728222.2016.1121236. Epub 2015 Dec 15.

Role of AMPK signaling in mediating the anticancer effects of silibinin in esophageal squamous cell carcinoma.

Li J1, Li B1,2,3, Xu WW1,2, Chan KW2,3,4, Guan XY3,5, Qin YR6, Lee NP3,7, Chan KT7, Law S3,7, Tsao SW1,3, Cheung AL1,2,3.

Author information

1
a School of Biomedical Sciences, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Pokfulam , Hong Kong SAR , China.
2
b The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI) , Hong Kong , China.
3
c Centre for Cancer Research , The University of Hong Kong , Pokfulam , Hong Kong SAR , China.
4
d Department of Pathology , The University of Hong Kong , Pokfulam , Hong Kong SAR , China.
5
e Department of Clinical Oncology, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Pokfulam , Hong Kong SAR , China.
6
f Department of Clinical Oncology, First Affiliated Hospital , Zhengzhou University , Zhengzhou , China.
7
g Department of Surgery, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Pokfulam , Hong Kong SAR , China.

Abstract

OBJECTIVE:

Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK) may suppress cancer growth. Identification of novel AMPK activators is therefore crucial to exploit AMPK as a potential target for cancer prevention and treatment.

RESEARCH DESIGN AND METHODS:

We determined the expression status and role of AMPK in esophageal squamous cell carcinoma (ESCC) and investigated whether silibinin, a nontoxic natural product, could activate AMPK to inhibit ESCC development.

RESULTS:

Our results from 49 pairs of human ESCC and normal tissues showed that AMPK was constitutively inactive in the majority (69.4%) of ESCC. We found that silibinin induced apoptosis, and inhibited ESCC cell proliferation in vitro and tumorigenicity in vivo without any adverse effects. Silibinin also markedly suppressed the invasive potential of ESCC cells in vitro and their ability to form lung metastasis in nude mice. The anticancer effects of silibinin were abrogated by the presence of compound C or shRNA against AMPK. More importantly, silibinin enhanced the sensitivity of ESCC cells and tumors to the chemotherapeutic drugs, 5-fluorouracil and cisplatin.

CONCLUSIONS:

This preclinical study supports that AMPK is a valid therapeutic target and suggests that silibinin may be a potentially useful therapeutic agent and chemosensitizer for esophageal cancer.

KEYWORDS:

AMPK; cancer progression; esophageal cancer; silibinin

PMID:
26568207
DOI:
10.1517/14728222.2016.1121236
[Indexed for MEDLINE]

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