合成的新茶氨酸衍生物茶双溴香酰胺对人乳腺癌细胞生长的抑制作用

Inhibitory effects of a novel theanine derivative DTBrC on the growth of human breast cancer cells

为提高茶氨酸的活性,开发新型抗肿瘤药物,合成了新的茶氨酸衍生物茶双溴香酰胺(DTBr C),比较茶氨酸和茶双溴香酰胺对高转移的人乳腺癌MDA-MB-231细胞生长的抑制作用与其分子机制。采用MTT方法检测不同浓度的DTBr C对MDA-MB-231细胞生长的影响,应用蛋白质印迹法检测解析MDA-MB-231细胞中与凋亡和生长密切相关蛋白的表达和药物可能的作用靶点。结果表明,DTBr C抑制MDA-MB-231细胞生长的活性超过其母体化合物茶氨酸多倍;DTBr C显著减少抗凋亡蛋白Bcl-2水平,大大提高促凋亡蛋白Bax表达,从而减少Bcl-2/Bax比率;此外,DTBr C明显抑制血管内皮生长因子受体VEGFR2和蛋白激酶Akt的表达及磷酸化,DTBr C对这些蛋白的作用活性强于茶氨酸。DTBr C作用机制可能与抑制MDA-MB-231细胞VEGFR2-Akt信号传导通路相关。本研究结果提示,DTBr C可能具有广泛应用于临床治疗和(或)辅助治疗高转移乳腺癌的潜力。

In order to develop new anticancer drugs, we synthesized a novel theanine derivative DTBrC and investigated the inhibitory effects of DTBrC on the growth of highly metastatic human breast cancer MDA-MB-231 cells and the mechanisms of action. The MTT assay was used to evaluate the in vitro effects of different concentrations of DTBrC on the grown of MDA-MB-231 cells. Western blotting was employed to ana- lyze the protein expressions and the possible targets of action related to the growth inhibition in MDA-MB-231 cells treated with DTBrC cells. The experimental results showed that DTBrC enhanced the growth inhibition of MDA-MB-231 cells by multifold as compared with theanine. DTBrC decreased the expression of antiapoptotic Bcl-2 protein and increased the level of proapoptotic Bax protein, resulting in reduction of Bcl-2/Bax ratio. Moreover, DTBrC greatly reduced the levels of VEGFR2 receptor protein and Akt kinase as well as Akt phos- phorylation. DTBrC exhibited much stronger activity than theanine on the regulation of these protein expressions relevant to the mechanism of action for repression the growth of MDA-MB-231 ceils. All these results suggested that DTBrC may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of highly- me- tastatic human breast cancer.