Houttuyninum, an active constituent of Chinese herbal medicine, inhibits phosphorylation of HER2/neu receptor tyrosine kinase and the tumor growth of HER2/neu-overexpressing cancer cells.

Abstract

AIMS:

The overexpression of HER2/neu receptor plays a key role in tumorigenesis and tumor progression. Small molecules targeting HER2/neu have therapeutic value in cancers that overexpress HER2. In this present study, the effect of houttuyninum, a component in the Chinese herbal medicine Houttuynia cordata Thunb, on HER2/neu tyrosine phosphorylation and its in vivo antitumour activity was investigated.

MAIN METHODS:

The phosphorylation and expression of proteins were determined by Western blot analysis. The MTT assay was employed to examine the inhibition of cell proliferation in vitro. Xenografts were established in nude mice for evaluating the antitumour activity of houttuyninum in vivo.

KEY FINDINGS:

Houttuyninum inhibited phosphorylation of HER2 in a dose-dependent manner with an IC50 of 5.52 μg/ml without reducing HER2/neu protein expression in MDA-MB-453 cells. Houttuyninum also inhibited the activation of ERK1/2 and AKT, downstream molecules in the HER2/neu-mediated signal transduction pathway. In contrast, tyrosine phosphorylation of EGFR was unaffected when the concentration of houttuyninum was increased to 40 μg/ml in both A431 cells and MDA-MB-468 cells. Additionally, houttuyninum preferentially inhibited the growth of MDA-MB-453 cells that overexpressed HER2/neu; the MDA-MB-468 cells that overexpress EGFR remained unaffected. Administration of houttuyninum in vivo resulted in a significant reduction of phosphorylated HER2 levels and in tumor volumes of the BT474 and N87 xenografts, which both overexpress HER2/neu.

SIGNIFICANCE:

Our findings showed that houttuyninum can inhibit the HER2/neu signalling pathway and the tumor growth of cancer cells that overexpress HER2/neu. This drug may provide therapeutic value in the treatment of cancers that involve overexpression of HER2/neu.

• Authors: Ning-Ning Zhou, Jun Tang, Wen-Dan Chen, Gong-Kan Feng, Bin-Fen Xie, Zong-Chao Liu, Dajun Yang, Xiao-Feng Zhu
• Journal: Life sciences (Life Sci) Vol. 90 Issue 19-20 Pg. 770-5 (May 22 2012) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 22525372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012. Published by Elsevier Inc.

Chemical References

• Drugs, Chinese Herbal
• HSP70 Heat-Shock Proteins
• houttuyninum
• ERBB2 protein, human
• ErbB Receptors
• Receptor Protein-Tyrosine Kinases
• Receptor, ErbB-2
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal (pharmacology)
• Enzyme Activation (drug effects)
• ErbB Receptors (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• HSP70 Heat-Shock Proteins (biosynthesis)
• Humans
• Mice
• Mice, Nude
• Oncogene Protein v-akt (metabolism)
• Phosphorylation (drug effects)
• Receptor Protein-Tyrosine Kinases
• Receptor, ErbB-2 (antagonists & inhibitors, biosynthesis, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays