title: Meso-dihydroguaiaretic acid induces apoptosis and inhibits cell migration via p38 activation and EGFR/Src/intergrin β3 downregulation in breast cancer cells.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Obstetrics & Gynecology, College of Traditional Korean Medicine, Dongguk University, Gyeongju, Republic of Korea.
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Choi
authors.affiliation: Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea.
authors.forename: Ha Jin
authors.initials: HJ
authors.lastname: Jeong
authors.affiliation: Natural Product Bank of Korea Promotion Institute for Traditional Medical Industry, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Natural Product Bank of Korea Promotion Institute for Traditional Medical Industry, Gyeongsangbuk-do, Republic of Korea; Department of Internal Medicine, Graduate School of Oriental Medicine, Dongguk University International Hospital, 814, Siksa-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-773, Republic of Korea.
authors.forename: Heung-Mook
authors.initials: HM
authors.lastname: Shin
authors.affiliation: Department of Biomedical Engineering, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Seung Tack
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Department of Biomedical Engineering, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Dongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea. Electronic address: jsong0304@dongguk.edu.
authors.forename: Songhee
authors.initials: S
authors.lastname: Jeon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016391:Genes, src / Q000187:drug effects; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis / Q000235:genetics; D017705:Lignans / Q000494:pharmacology*; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D039661:Integrin beta3; D017705:Lignans; C015816:dihydroguaiaretic acid; D006139:Guaiacol; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 4T-1 cells; Breast cancer; Caspase-3; Intergrin β3; Meso-dihydroguaiaretic acid; p38