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

Abstract

AIM:

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.

CONCLUSION:

Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.

• Authors: Xi-wei Ji, Run-tao Li, Zai-quan Li, Liang Li, Xue-yan Shao, Si-yuan Wang, Yin Yuan, Tian-yan Zhou, Wei Lu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 35 Issue 2 Pg. 239-47 (Feb 2014) ISSN: 1745-7254 [Electronic] United States
• PMID: 24374811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride
• Piperazines
• ErbB Receptors

Topics

• Animals
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation (drug effects)
• Piperazines (pharmacology)