Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn., represses hepatocellular carcinoma cell migration and metastasis: the role of hypoxia inducible factor 1 pathway.

Abstract

Brucine is an alkaloid derived from the seeds of Strychnos nux-vomica Linn. which have long been used as a traditional medicine for the treatment of hepatocellular carcinoma (HCC) in China. HCC prognosis can be greatly influenced by metastasis. There has thus far been little research into brucine as a source of anti-metastasis activity against HCC. In this study, we revealed that brucine dramatically repressed HepG2 and SMMC-7721 HCC cell migration with few cytotoxic effects. Hypoxia inducible factor 1 (HIF-1) is a key transcription factor mediating cell migration and invasion. Brucine suppressed HIF-1-dependent luciferase activity in HepG2 cells. The transcriptions of four known HIF-1 target genes involved in HCC metastasis, i.e., fibronectin, matrix metallopeptidase 2, lysyl oxidase, and cathepsin D, were also attenuated after brucine treatment. Experiments in vivo showed that an intraperitoneal injection of 5 and 15 mg/kg of brucine resulted in dose-dependent decreases in the lung metastasis of H22 ascitic hepatoma cells. Moreover, a dosage of brucine at 15 mg/kg exhibited very low toxic effects to tumor-bearing mice. Consistently, brucine downregulated expression levels of HIF-1 responsive genes in vivo. Our current study demonstrated the capacity of brucine in suppressing HCC cell migration in vitro and lung metastasis in vivo. The inhibition of the HIF-1 pathway is implicated in the anti-metastasis activity of brucine.

• Authors: Guangwen Shu, Xue Mi, Jian Cai, Xinlin Zhang, Wu Yin, Xinzhou Yang, You Li, Lvyi Chen, Xukun Deng
• Journal: Toxicology letters (Toxicol Lett) Vol. 222 Issue 2 Pg. 91-101 (Oct 24 2013) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 23933019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Hypoxia-Inducible Factor 1
• Neoplasm Proteins
• brucine
• Strychnine

Topics

• Animals
• Animals, Outbred Strains
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, secondary)
• Cell Line, Tumor
• Cell Movement (drug effects)
• China
• Dose-Response Relationship, Drug
• Ethnopharmacology
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1 (antagonists & inhibitors, genetics, metabolism)
• Liver Neoplasms (drug therapy)
• Lung Neoplasms (prevention & control, secondary)
• Male
• Mice
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Random Allocation
• Seeds (chemistry)
• Strychnine (administration & dosage, adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Strychnos nux-vomica (chemistry)
• Xenograft Model Antitumor Assays