Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status.
Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status.
复制标题
DOI：
10.1371/journal.pone.0142928
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Palau VE
中科院分区：
文献类型：
--
作者：
LeJeune TM;Tsui HY;Parsons LB;Miller GE;Whitted C;Lynch KE;Ramsauer RE;Patel JU;Wyatt JE;Street DS;Adams CB;McPherson B;Tsui HM;Evans JA;Livesay C;Torrenegra RD;Palau VE
细胞凋亡可以通过两种不同的方式触发，通过内在或外在途径。内源性途径由线粒体通过释放细胞色素C介导，而外源性途径由死亡受体信号促进并绕过线粒体。这两种途径与细胞增殖和生存信号级联密切相关，因此构成了癌症治疗的可能靶点。在以前的研究中，我们介绍了两种植物衍生的异构体黄酮类化合物，黄酮A和黄酮B，它们在乳腺、结肠、胰腺和前列腺的高度致瘤性癌细胞中诱导凋亡。黄酮A对结肠（CaCo-2）和胰腺（Panc 28）的更高分化的癌显示出有效的细胞毒活性，而黄酮B的细胞毒作用在结肠（HCT 116）和胰腺（MIA PaCa）的低分化癌上观察到。在分化较好的结肠癌CaCo-2和胰腺癌Panc 28细胞中，黄酮A通过抑制细胞外信号调节激酶（ERK）和pS 6的活化形式以及随后Bcl-2相关死亡启动子（BAD）蛋白的磷酸化的丧失，经由内源性途径诱导细胞凋亡，而在低分化结肠癌HCT 116和MIA PaCa胰腺癌细胞中，黄酮B通过伴随ERK和c-磷酸化形式的上调的外源性途径触发凋亡。73.第73章.这些蛋白质水平的变化最终导致细胞凋亡的激活，而不涉及AKT。
Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT.