Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Acta Pharmacol Sin. 2014 Feb;35(2):239-47. doi: 10.1038/aps.2013.156. Epub 2013 Dec 30.
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.
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.
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.
Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.
研究新型二硫代氨基甲酸盐衍生物 TM208 对人乳腺癌细胞的作用及其在人乳腺癌异种移植瘤小鼠体内的药代动力学特征。
用 TM208 或阳性对照药物他莫昔芬处理人乳腺癌 MCF-7 和 MDA-MB-231 细胞。采用 SRB 和集落形成实验检测细胞增殖。采用 Annexin V-FITC/PI 染色法分析细胞凋亡。采用 Western blot、ELISA 和免疫组织化学分析检测蛋白表达。MCF-7 乳腺癌异种移植裸鼠经口给予 TM208（50 或 150 mg·kg(-1)·d(-1))或他莫昔芬（50 mg·kg(-1)·d(-1))18 d。第 19 天，收集肿瘤进行分析。从给予 TM208 高剂量的小鼠中采集血样，并用 LC-MS/MS 测定 TM208 的血浆浓度。
TM208 处理 MCF-7 和 MDA-MB-231 细胞，体外剂量依赖性地抑制细胞增殖和集落形成（IC50 值分别为 36.38±3.77 和 18.13±0.76 μmol/L）。TM208（20-150 μmol/L）体外剂量依赖性地诱导两种乳腺癌细胞凋亡。在 MCF-7 乳腺癌异种移植裸鼠中，TM208 给药剂量依赖性地降低肿瘤生长，但未导致 TM208 蓄积或体重减轻。TM208 体外剂量依赖性地抑制乳腺癌细胞中 EGFR 和 ERK1/2 的磷酸化，以及 MCF-7 异种移植瘤中的磷酸化。
抑制 EGFR 自身磷酸化在 TM208 抑制人乳腺癌中的抗癌作用中起重要作用。
