Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208

• Published in: Acta pharmacologica Sinica Vol. 35; no. 2; pp. 239 - 247
• Main Authors: Ji, Xi-wei, Li, Run-tao, Li, Zai-quan, Li, Liang, Shao, Xue-yan, Wang, Si-yuan, Yuan, Yin, Zhou, Tian-yan, Lu, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2014; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line, Tumor; Female; Humans; Immunology; Internal Medicine; LC-MS; MCF-7 Cells; Medical Microbiology; Mice; Mice, Inbred BALB C; Mice, Nude; Original; original-article; Pharmacology/Toxicology; Phosphorylation - drug effects; Piperazines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Vaccine; Western印迹; 二硫代氨基甲酸; 人乳腺癌细胞; 异种移植; 自磷酸化; 衍生物; 表皮生长因子受体; TM208; ERK1/2; tumor xenograft nude mice; breast cancer; dithiocarbamate; tyrosine kinase inhibitor; phosphorylation; EGFR
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/aps.2013.156

Aim： To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacoki- netic 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 pro- liferation 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.k$1〈1-1） or tamoxifen （50 mg.kgl〈t-~） 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 IC~o values were 36.38＋3.77 and 18.13＋0.76 pmol/L, respectively）. TM208 （20-150pmol/L） dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-depend- ently 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. Conclusion： Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.