Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism.
Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism.
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DOI：
10.1016/j.bcp.2009.09.006
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发表时间：
2010-02-01
影响因子：
5.8
通讯作者：
Gautam, Subhash C.
中科院分区：
文献类型：
--
作者：
Deeb, Dorrah;Gao, Xiaohua;Jiang, Hao;Janic, Branislava;Arbab, Ali S.;Rojanasakul, Yon;Dulchavsky, Scott A.;Gautam, Subhash C.
CDDO-Me是一种由齐墩果酸衍生的合成三萜，是一种很有前途的抗癌药物，在体内和体外对多种癌症都有很强的活性。我们之前已经证明CDDO-Me诱导前列腺癌细胞凋亡，而不考虑其激素状态。为了进一步了解CDDO-Me的促凋亡机制，我们研究了活性氧（ROS）在LNCaP和PC-3前列腺癌细胞中介导CDDO-Me诱导凋亡活性的作用。在这里，我们发现CDDO-Me诱导非线粒体和线粒体来源的ROS生成，这与诱导凋亡有关，其特征是膜联蛋白v结合增加，PARP-1和procaspase -3，-8， -9的切割，线粒体膜电位的丧失和细胞色素c的释放。此外，CDDO-Me抑制细胞存活Akt， NF-κB和mTOR信号蛋白。n -乙酰半胱氨酸（NAC）或过表达抗氧化酶谷胱甘肽过氧化物酶（GPx）和超氧化物歧化酶（SOD1）对ROS生成的抑制作用可阻止cddo - me诱导的细胞凋亡。NAC预处理阻断膜联蛋白v结合，阻断PARP-1和procaspase -3、-8、-9的裂解，阻断线粒体膜电位的丧失，阻断CDDO-Me释放细胞色素c。NAC还能阻止CDDO-Me对组成型活性Akt、NF-κB和mTOR的抑制作用。综上所述，这些数据表明ROS在CDDO-Me诱导前列腺癌细胞凋亡中起重要作用。
CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases -3,-8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-κB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase1 (SOD1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V-binding, cleavage of PARP-1 and procaspases -3,-8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-κB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in induction of apoptosis by CDDO-Me in prostate cancer cells.
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影响因子：
6.6
作者：
Fleshner, Neil;Bagnell, P. Scott;Venkateswaran, Vasundara
通讯作者：
Venkateswaran, Vasundara
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1073/pnas.0506893102
发表时间：
2005-11-22
影响因子：
11.1
作者：
Gao, JJ;Liu, XP;Rigas, B
通讯作者：
Rigas, B
影响因子：
2.7
作者：
Honda, T;Rounds, BV;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J