MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis via a Reactive Oxygen Species- and Caspase-Dependent Mitochondrial Pathway
MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis via a Reactive Oxygen Species- and Caspase-Dependent Mitochondrial Pathway
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DOI：
10.1124/jpet.107.135657
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发表时间：
2008-06
影响因子：
3.5
通讯作者：
Meidan Ying;Chongxing Tu;Huazhou Ying;Yongzhou Hu;Qiaojun He;Bo Yang
中科院分区：
文献类型：
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作者：
Meidan Ying;Chongxing Tu;Huazhou Ying;Yongzhou Hu;Qiaojun He;Bo Yang
肝细胞癌是肝脏最常见的恶性肿瘤。不幸的是，肝癌对常规化疗、放射治疗甚至免疫治疗都高度耐药。因此，需要寻找新的治疗靶点来成功治疗肝癌。我们现在报道合成的黄烷酮衍生物(±)-(3aRS，4SR)-2-(2-chloro-4-methylsulfonylphenyl)-4′-chloro-3α，4-diethoxy-flavane[4，3-d]-D1，9b-1，2，3-thiadiazoline在体外和体内都能诱导肝癌细胞的生长停滞和凋亡。MSFTZ通过激活caspase-3和裂解聚(ADP-核糖)聚合酶-1，诱导时间和剂量依赖的肝癌细胞凋亡增加。MSFTZ诱导的caspase-9激活提示，MSFTZ诱导的信号转导是通过线粒体死亡途径实现的。此外，我们观察到活性氧物种(ROS)的升高和线粒体膜电位的丧失，进一步表明MSFTZ诱导的死亡信号是通过线粒体氧应激途径介导的。这些事件分别与Bcl2和Bax的表达降低和Bax表达增加，以及丝裂原活化蛋白激酶(MAPK)的磷酸化和P53-MDM2通路的激活有关。然而，抗氧化剂N-乙酰半胱氨酸对抗MSFTZ介导的线粒体功能障碍、caspase激活、Bcl2/Bax调控和细胞凋亡，支持ROS在细胞凋亡过程中的作用。令我们惊讶的是，我们没有观察到N-乙酰半胱氨酸对MSFTZ诱导的MAPK激活的保护作用。此外，MSFTZ在体内对SMMC-7721裸鼠移植瘤的抑瘤率为34.8%~78.7%。我们得出结论：MSFTZ通过依赖caspase和ROS的线粒体途径在体内和体外诱导肝癌细胞凋亡。此外，MSFTZ有可能成为治疗肝癌的一种新的治疗剂。
Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. It is unfortunate that HCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of HCCs. We now report that (±)-(3aRS,4SR)-2-(2-chloro-4-methylsulfonylphenyl)-4′-chloro-3α,4-diethoxy-flavane[4,3-d]-D1,9b-1,2,3-thiadiazoline (MSFTZ), a synthesized flavanone derivative, induced growth arrest and apoptosis of HCCs both in vitro and in vivo. MSFTZ induced a time- and dose-dependent increase in HCC apoptosis through caspase-3 activation and poly(ADP-ribose) polymerase-1 cleavage. Activation of caspase-9 induced by MSFTZ suggested that MSFTZ-induced signaling was mediated through a mitochondrial death pathway. In addition, we observed an elevation of reactive oxygen species (ROS) and a consequent loss of mitochondrial membrane potential, further suggesting that MSFTZ-induced death signaling was mediated through a mitochondrial oxygen stress pathway. These events were associated with a decrease and increase in Bcl-2 and Bax expression, respectively, as well as phosphorylation of mitogen-activated protein kinase (MAPK) and activation of p53-MDM2 pathway. However, the antioxidant N-acetylcysteine opposed MSFTZ-mediated mitochondrial dysfunction, caspase activation, Bcl-2/Bax modulation, and apoptosis, supporting the role of ROS in the apoptotic process. We were surprised that we failed to observe the protective effect of N-acetylcysteine against MSFTZ-induced MAPK activation. Furthermore, MSFTZ had an antitumor effect in vivo by 34.8 to 78.7% reduction of tumor size in SMMC-7721-xenografted nude mice. We conclude that MSFTZ induces HCC cell apoptosis both in vivo and in vitro via caspase- and ROS-dependent mitochondrial pathway. In addition, MSFTZ has potential as a novel therapeutic agent for the treatment of HCC.