Molecular mechanism of cancer chemoprevention by anthocyanins

花青素是花青素的配基核，花青素是一种红色色素，广泛存在于有色水果和蔬菜中。为了研究花色苷的抗癌作用，我们用人早幼粒白血病细胞(HL-60)进行了诱导细胞凋亡的实验，这是检测抗白血病或一般抗肿瘤化合物的有效模型。在代表大多数花色素苷元的六种花青素中，只有B环上具有邻二羟基苯基结构的花青素才能诱导细胞凋亡，这表明花青素的邻二羟基苯基结构可能有助于诱导细胞凋亡。Delphinidin是最有效的诱导剂，以时间和剂量依赖的方式诱导细胞凋亡。在100μM作用6h后，可有效地诱导细胞凋亡。在诱导细胞凋亡的同时，飞雀素还能刺激jnk通路的激活，包括jnk的磷酸化和c-jun基因的表达，并激活caspase-3。抗氧化剂包括N-乙酰-L半胱氨酸(NAC)和过氧化氢酶(CAT)有效地阻断了Delphinidin诱导的JNK的磷酸化、caspase-3的激活和DNA片段化。此外，花青素直接导致HL-60细胞产生细胞内过氧化氢。因此，花青素可能通过氧化应激参与的JNK信号通路触发细胞的凋亡死亡程序。花色苷诱导细胞凋亡可能是其抗癌化学预防作用的关键机制。

Anthocyanidins are the aglycon nucleuses of anthocyanins, which are reddish pigments widely spread in colored fruits and vegetables. To investigate the anti-cancer effect of anthocyanins, induction of apoptosis was tested in human promyelocytic leukemia cells (HL-60), which is a valid model for testing antileukemic or general antitumoral compounds. Of six anthocyanidins representing the aglycons of most of anthocyanins, only those with an ortho-dihydroxyphenyl structure on the B-ring induce apoptosis, suggesting that the ortho-dihydroxyphenyl structure of anthocyanidins may contribute to the induction of apoptosis. Delphinidin, the most potent inducer, causes apoptosis in a time-and dose-dependent manner. The efficacious induction of apoptosis was observed at 100 μM for 6 h. Concomitant with the apoptosis, delphinidin stimulates JNK pathway activation including JNK phosphorylation and c-jun gene expression, and activates caspase-3. Antioxidants including N-acetyl-L-cysteine (NAC) and catalase effectively block delphinidin-induced JNK phosphorylation, caspase-3 activation, and DNA fragmentation. Moreover, anthocyanidins directly cause HL-60 cells to generate intracellular hydrogen peroxide. Thus, anthocyanidins may trigger an apoptotic death program through an oxidative stress-involved JNK signaling pathway. The induction of apoptosis by anthocyanins may be the pivotal mechanism by which its chemopreventive action against cancer is based.