Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Zhejiang University, Hangzhou, PR China.
Chemotherapy. 2011;57(2):162-72. doi: 10.1159/000326915. Epub 2011 Mar 31.
BACKGROUND/AIMS: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives.
Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity.
Among the 6 derivatives, 3,5-dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC(50) value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl.
DMFC is potentially an effective therapeutic agent in liver cancer therapy.
背景/目的：香豆素是存在于许多植物中的天然化合物，本身及其修饰衍生物具有药用价值。
合成了 6 种新型香豆素衍生物，并对其潜在的抗癌细胞毒性进行了检测。
在 6 种衍生物中，3,5-二甲基-(7)H-呋喃并[3,2-g]色烯-7-酮（DMFC）在体外对人肝癌 HepG2 细胞表现出最强的细胞毒性，在 48 小时处理中 IC50 值为 8.46±0.28 μM。进一步的实验表明，DMFC 通过依赖 p53 的外在和内在凋亡途径诱导 HepG2 细胞凋亡。在机制上，DMFC 激活了半胱天冬酶 3、8 和 9，使线粒体膜电位去极化，并诱导细胞色素 c 和凋亡诱导因子的释放。DMFC 诱导的凋亡也表现为 DNA 片段化、磷脂酰丝氨酸外翻和 DNA 直方图中的 sub-G1 峰。此外，半胱天冬酶 8 和 9 的抑制剂均能抑制 DMFC 诱导的凋亡。Western blot 分析表明，DMFC 还显著增加了 p53、Fas 死亡受体、Fas 相关死亡结构域蛋白和促凋亡 Bcl-2 家族成员（如 Bax、Bad 和 tBid）的表达水平，同时降低了抗凋亡成员（如 Bcl-2 和 Bcl-xl）的水平。
DMFC 可能是肝癌治疗的有效治疗剂。
