Department of Biochemistry, Dongeui University College of Oriental Medicine, Yangjung-Dong, Busanjin-Gu, Busan 614-714, South Korea.
Anticancer Res. 2009 Nov;29(11):4457-65.
Sanguinarine is a benzophenanthridine alkaloid, derived from the root of Sanguinaria canadensis and other poppy Fumaria species, which is known to have antimicrobial, antiinflammatory and antioxidant properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells but spare most normal cells. However, its effects are limited in some types of cancer cells, including AGS human gastric adenocarcinoma cells. In the present study, we showed that treatment with TRAIL in combination with subtoxic concentrations of sanguinarine sensitized TRAIL-mediated apoptosis in AGS cells. Combined treatment with sanguinarine and TRAIL effectively induced Bid cleavage and loss of mitochondrial membrane potential, leading to the activation of caspases, and cleavage of poly(ADP-ribose) polymerase and beta-catenin. The cytotoxic effects of the combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. In addition, the levels of Akt protein were markedly reduced in cells co-treated with sanguinarine and TRAIL. Apoptosis induced by the combined treatment was markedly increased by the phosphatidylinositol-3'-kinase inhibitor, LY294002 (Akt-upstream inhibitor), through the mitochondrial amplification step and caspase activation, suggesting that interactions of the synergistic effect were at least partially mediated through the Akt-dependent pathway.
血根碱是一种苯并菲啶生物碱，来源于白屈菜属植物的根和罂粟科其他款冬属植物，具有抗菌、抗炎和抗氧化特性。肿瘤坏死因子相关凋亡诱导配体（TRAIL）已知能诱导癌细胞凋亡而使大多数正常细胞免受伤害。然而，其在某些类型的癌细胞中的作用有限，包括AGS 人胃腺癌细胞。在本研究中，我们发现 TRAIL 联合亚毒性浓度血根碱处理能增敏 TRAIL 诱导的 AGS 细胞凋亡。联合处理血根碱和 TRAIL 能有效诱导 Bid 裂解和线粒体膜电位丧失，导致 caspase 激活和多聚（ADP-核糖）聚合酶和β-连环蛋白的裂解。联合处理的细胞毒性作用明显被 z-DEVD-fmk 抑制，即 caspase-3 抑制剂，这表明 caspase-3 在观察到的细胞毒性作用中起着重要作用。此外，在血根碱和 TRAIL 共同处理的细胞中，Akt 蛋白的水平明显降低。通过磷脂酰肌醇-3'-激酶抑制剂 LY294002（Akt 上游抑制剂），联合处理诱导的凋亡明显增加，通过线粒体扩增步骤和 caspase 激活，表明协同作用的相互作用至少部分通过 Akt 依赖途径介导。
