Meso-dihydroguaiaretic acid induces apoptosis and inhibits cell migration via p38 activation and EGFR/Src/intergrin β3 downregulation in breast cancer cells.

Abstract

AIMS:

Meso-dihydroguaiaretic acid (MDA) is known for its anti-inflammatory, anti-oxidant, anti-bacterial, and anti-tumor activity. However, the anti-breast cancer effect and the mechanism of MDA remain undefined.

MAIN METHODS:

In this study, we examined the anti-cancer activity and the mechanisms of action of MDA in breast cancer cell lines, 4T-1 and MCF-7 cells; and 4T-1 bearing mouse model.

KEY FINDINGS:

MDA showed cytotoxic effects on 4T-1 and MCF-7 cells in a dose-dependent manner. Moreover, MDA increased the amount of Annexin V-positive apoptotic bodies, phosphorylated JNK and p38 in 4T-1 cells. MDA also down-regulated cell-cycle dependent proteins, CDK-4 and cyclin D1; and induced cleaved caspase-3 in MDA-treated 4T-1 cells. We further verified that MDA-induced apoptosis is mediated by p38 and caspase-3 activation in 4T-1 cells. Next, we studied the effect of MDA treatment on cell migration and found that MDA significantly reduced cell migration. Moreover, MDA reduced EGFR and intergrin β3 expression, and dephosphorylated Src in a dose-dependent manner in 4T-1 cells. Furthermore, we observed in vivo effect of MDA in 4T-1 cell inoculated mice. MDA (20mg/kg/day) significantly suppressed mammary tumor volume and activated caspase-3 in tumor tissues.

SIGNIFICANCE:

These results suggest novel targets of MDA in breast cancer in vitro and in vivo, making it a potential candidate as a chemotherapeutic drug.

• Authors: Min Sun Choi, Ha Jin Jeong, Tae-Hoon Kang, Heung-Mook Shin, Seung Tack Oh, Yura Choi, Songhee Jeon
• Journal: Life sciences (Life Sci) Vol. 141 Pg. 81-9 (Nov 15 2015) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26382595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Integrin beta3
• Lignans
• dihydroguaiaretic acid
• Guaiacol
• ErbB Receptors
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• ErbB Receptors (biosynthesis, genetics)
• Female
• Genes, src (drug effects)
• Guaiacol (analogs & derivatives, pharmacology)
• Humans
• Integrin beta3 (biosynthesis, genetics)
• Lignans (pharmacology)
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• p38 Mitogen-Activated Protein Kinases (drug effects)