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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / drug effects*
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Fluorouracil / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / prevention & control
  • Signal Transduction / drug effects
  • Silybin
  • Silymarin / administration & dosage
  • Silymarin / pharmacology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Silymarin
  • Silybin
  • AMP-Activated Protein Kinases
  • Fluorouracil