Horinaka Mano, Yoshida Tatsushi, Shiraishi Takumi, Nakata Susumu, Wakada Miki, Sakai Toshiyuki
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto 602-8566, Japan.
Mol Cancer Ther. 2006 Apr;5(4):945-51. doi: 10.1158/1535-7163.MCT-05-0431.
Dietary flavonoid apigenin is expected to have preventive and therapeutic potential against malignant tumors. In this report, we show for the first time that apigenin markedly induces the expression of death receptor 5 (DR5) and synergistically acts with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in malignant tumor cells. TRAIL is a promising candidate for cancer therapeutics due to its ability to selectively induce apoptosis in cancer cells. The combined use of apigenin and TRAIL at suboptimal concentrations induces Bcl-2-interacting domain cleavage and the activation of caspases-8, -10, -9, and -3. Furthermore, human recombinant DR5/Fc chimera protein and caspase inhibitors dramatically inhibit apoptosis induced by the combination of apigenin and TRAIL. On the other hand, apigenin-mediated induction of DR5 expression is not observed in normal human peripheral blood mononuclear cells. Moreover, apigenin does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis. These results suggest that this combined treatment with apigenin and TRAIL might be promising as a new therapy against malignant tumors.
膳食类黄酮芹菜素有望对恶性肿瘤具有预防和治疗潜力。在本报告中，我们首次表明芹菜素显著诱导死亡受体5（DR5）的表达，并与外源性可溶性重组人肿瘤坏死因子相关凋亡诱导配体（TRAIL）协同作用，诱导恶性肿瘤细胞凋亡。TRAIL因其能够选择性地诱导癌细胞凋亡，是一种很有前景的癌症治疗候选药物。在次优浓度下联合使用芹菜素和TRAIL可诱导Bcl-2相互作用结构域裂解以及半胱天冬酶-8、-10、-9和-3的激活。此外，人重组DR5/Fc嵌合蛋白和半胱天冬酶抑制剂可显著抑制芹菜素和TRAIL联合诱导的凋亡。另一方面，在正常人外周血单个核细胞中未观察到芹菜素介导的DR5表达诱导。此外，芹菜素不会使正常人外周血单个核细胞对TRAIL诱导的凋亡敏感。这些结果表明，芹菜素和TRAIL的联合治疗可能作为一种治疗恶性肿瘤的新疗法具有前景。
