Ma Zengshuan, Molavi Ommoleila, Haddadi Azita, Lai Raymond, Gossage Robert A, Lavasanifar Afsaneh
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Cancer Chemother Pharmacol. 2008 Dec;63(1):27-35. doi: 10.1007/s00280-008-0704-z. Epub 2008 Feb 20.
Resveratrol is a well-known chemopreventive and chemotherapeutic agent. Among all of the resveratrol analogs synthesized, 3,4,5,4'-tetramethoxystilbene (DMU-212) shows high activity and selectivity against various cancer cell types. The objective of this study is to investigate why DMU-212 has higher anti-tumor activity than resveratrol.
The effects of DMU-212 and resveratrol on cell viability, cell cycle, Stat3 activation, and microtubule dynamic were investigated and compared using MTT assay, cell cycle analysis, Western blot, tubulin polymerization assay, respectively, in MDA-MB-435 and MCF-7 human breast cancer cells.
Compared to resveratrol, DMU-212 exerted a significantly higher growth inhibition in both cell lines. Further studies demonstrated that DMU-212 acted via different mechanisms from resveratrol. First, DMU-212 induced predominantly G2/M arrest whereas resveratrol induced G0/G1 arrest in both cell lines. Correlating with these findings, resveratrol induced more dramatic changes in the expression of Cyclin D1 compared to DMU-212. Second, DMU-212 induced apoptosis and reduced the expression of multiple anti-apoptotic proteins more appreciably than resveratrol. Third, while both agents inhibited Stat3 phosphorylation, treatments of DMU-212 but not resveratrol led to a significant increase in tubulin polymerization. The higher sensitivity to DMU-122 in MDA-MB-435 correlated with the more prominent effects seen in these parameters in this cell line, as compared to MCF7.
Compared to resveratrol, the novel stilbene derivative, DMU-212, had higher anti-tumor effects, which are likely owing to its modulation of multiple cellular targets.
白藜芦醇是一种著名的化学预防和化疗药物。在所有合成的白藜芦醇类似物中，3,4,5,4'-四甲氧基二苯乙烯（DMU-212）对多种癌细胞类型显示出高活性和选择性。本研究的目的是探究为何DMU-212比白藜芦醇具有更高的抗肿瘤活性。
分别使用MTT法、细胞周期分析、蛋白质免疫印迹法、微管蛋白聚合试验，研究并比较DMU-212和白藜芦醇对MDA-MB-435和MCF-7人乳腺癌细胞的细胞活力、细胞周期、Stat3激活及微管动力学的影响。
与白藜芦醇相比，DMU-212在两种细胞系中均表现出显著更高的生长抑制作用。进一步研究表明，DMU-212与白藜芦醇的作用机制不同。首先，DMU-212主要诱导G2/M期阻滞，而白藜芦醇在两种细胞系中均诱导G0/G1期阻滞。与这些发现相关的是，与DMU-212相比，白藜芦醇诱导细胞周期蛋白D1的表达发生更显著的变化。其次，DMU-212诱导细胞凋亡，并比白藜芦醇更明显地降低多种抗凋亡蛋白的表达。第三，虽然两种药物均抑制Stat3磷酸化，但DMU-212处理而非白藜芦醇处理导致微管蛋白聚合显著增加。与MCF7相比，MDA-MB-435对DMU-122的更高敏感性与该细胞系中这些参数更显著的效应相关。
与白藜芦醇相比，新型二苯乙烯衍生物DMU-212具有更高的抗肿瘤作用，这可能归因于其对多个细胞靶点的调节作用。
