Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Mol Carcinog. 2010 May;49(5):464-75. doi: 10.1002/mc.20619.
Flavonoids are polyphenolic compounds which display a vast array of biological activities and are promising anticancer agents. In this study we investigated the effect of 5,7,3'-trihydroxy-3,4'-dimethoxyflavone (THDF) on viability of nine human tumor cell lines and found that it was highly cytotoxic against leukemia cells. THDF induced G(2)-M phase cell-cycle arrest and apoptosis through a caspase-dependent mechanism involving cytochrome c release, processing of multiple caspases (caspase-3, -6, -7, and -9) and cleavage of poly(ADP-ribose) polymerase. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-x(L) conferred partial resistance to THDF-induced apoptosis. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases (MAPKs) family and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) and of extracellular signal-regulated kinases (ERK) 1/2. In the present study we report that THDF-induced cell death is mediated by an intrinsic dependent apoptotic event involving mitochondria and MAPKs, and through a mechanism independent of the generation of reactive oxygen species. The results suggest that THDF could be useful in the development of novel anticancer agents.
类黄酮是具有广泛生物活性的多酚化合物，是很有前途的抗癌药物。在本研究中，我们研究了 5,7,3'-三羟基-3,4'-二甲氧基黄酮（THDF）对九个人类肿瘤细胞系活力的影响，发现它对白血病细胞具有高度细胞毒性。THDF 通过细胞色素 c 释放、多种半胱天冬酶（caspase-3、-6、-7 和 -9）的加工以及聚（ADP-核糖）聚合酶的切割，通过 caspase 依赖性机制诱导 G2-M 期细胞周期停滞和细胞凋亡。保护性线粒体蛋白 Bcl-2 和 Bcl-x(L) 的过表达赋予了 THDF 诱导的细胞凋亡部分抗性。这种类黄酮诱导丝裂原活化蛋白激酶（MAPKs）家族成员的磷酸化，细胞死亡通过抑制 c-jun N 末端激酶/应激激活蛋白激酶（JNK/SAPK）和细胞外信号调节激酶（ERK）1/2 而减弱。在本研究中，我们报告 THDF 诱导的细胞死亡是通过涉及线粒体和 MAPKs 的内在依赖性凋亡事件介导的，并且通过与活性氧生成无关的机制。结果表明，THDF 可用于开发新型抗癌药物。
