Synergistic Chemopreventive and Therapeutic Effects of Co-drug UA-Met: Implication in Tumor Metastasis.
Synergistic Chemopreventive and Therapeutic Effects of Co-drug UA-Met: Implication in Tumor Metastasis.
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DOI：
10.1021/acs.jafc.7b04378
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发表时间：
2017-12
影响因子：
6.1
通讯作者：
Guirong Zheng;Zhichun Shen;Aixiao Xu;Kai Jiang;Pengyu Wu;Xiang Yang;Xian Chen;Jingwei Shao
中科院分区：
文献类型：
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作者：
Guirong Zheng;Zhichun Shen;Aixiao Xu;Kai Jiang;Pengyu Wu;Xiang Yang;Xian Chen;Jingwei Shao
熊果酸（UA）和二甲双胍（Met）的抗癌特性已得到充分证明。然而，这些化合物是否可以协同作用以预防和治疗癌症尚不清楚。我们在这项研究中，UA和Met之间的协同作用，以及一种新的联合药物UA和Met（UA-Met）对几种癌细胞系。高浓度UA（25、50、75、100 μM）与Met（5、10、20、40 mM）联合作用对MDA-MB-231和MCF-7细胞具有协同细胞毒作用（CI < 0.8）。分子和细胞研究表明，在低浓度（10 μM）时，UA-Met对TGF-β诱导的乳腺癌MDA-MB-231和MCF-7细胞的侵袭和迁移均有明显的抑制作用（分别为抑制率55.3 ± 2.74%和抑制率52.4 ± 1.57%）。这些作用伴随着CXCR 4、uPA、波形蛋白、E-cadherin、N-cadherin和MMP-2/9蛋白表达的下调以及AMPK/m-TOR信号通路的调节，正如UA和Met所预期的那样。UA-Met能明显抑制4 T1细胞的肺转移（63.4 ± 3.52%），且不影响小鼠血糖水平。我们的研究表明，联合药物UA-Met在预防癌症转移和可能治疗癌症方面是安全有效的。
The anticancer properties of ursolic acid (UA) and metformin (Met) have been well demonstrated. However, whether these compounds can act synergistically to prevent and treat cancer is not known. We present in this study, the synergism between UA and Met, and that of a new codrug made of UA and Met (UA-Met) against several cancer cell lines. The combination of high concentration of UA (25, 50, 75, 100 μM) and Met (5, 10, 20, 40 mM) resulted in synergetic cytotoxicity on MDA-MB-231 and MCF-7 cells (CI < 0.8). Molecular and cellular studies showed that codrug UA-Met significantly inhibited the invasion (∼55.3 ± 2.74%) and migration (∼52.4 ± 1.57%) of TGF-β induced breast cancer MDA-MB-231 and MCF-7 cells in vitro at low concentration of 10 μM. These effects were accompanied by down-regulation of CXCR4, uPA, vimentin, E-cadherin, N-cadherin, and MMP-2/9 proteins expression and regulation of the AMPK/m-TOR signaling pathways as expected from UA and Met. Moreover, UA-Met could reduce the progression of pulmonary metastasis by 4T1 cells (63.4 ± 3.52%) without influencing the glucose blood level in mice. Our study suggests that the codrug UA-Met is safe and effective in preventing cancer metastasis and possibly treatment of cancer.