title: Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208.
abstract: OBJECTIVE
  To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacokinetic characteristics of TM208 in human breast cancer xenograft mice.
  
  
  METHODS
  Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell proliferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg·kg(-1)·d(-1)) or tamoxifen (50 mg·kg(-1)·d(-1)) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS.
  
  
  RESULTS
  Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC50 values were 36.38 ± 3.77 and 18.13 ± 0.76 μmol/L, respectively). TM208 (20-150 μmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-dependently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor.
  
  
  CONCLUSIONS
  Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Xi-wei
authors.initials: XW
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Run-tao
authors.initials: RT
authors.lastname: Li
authors.affiliation: Department of Radiation Medicine, Peking University, Beijing 100191, China.
authors.forename: Zai-quan
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Xue-yan
authors.initials: XY
authors.lastname: Shao
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Si-yuan
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: 1] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China [2] Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Tian-yan
authors.initials: TY
authors.lastname: Zhou
authors.affiliation: 1] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China [2] Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*
chemical_list: C522133:4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride; D010879:Piperazines; D066246:ErbB Receptors