An NQO1-initiated and p53-independent apoptotic pathway determines the anti-tumor effect of tanshinone IIA against non-small cell lung cancer.
An NQO1-initiated and p53-independent apoptotic pathway determines the anti-tumor effect of tanshinone IIA against non-small cell lung cancer.
复制标题
DOI：
10.1371/journal.pone.0042138
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hao H
中科院分区：
文献类型：
--
作者：
Liu F;Yu G;Wang G;Liu H;Wu X;Wang Q;Liu M;Liao K;Wu M;Cheng X;Hao H
NQO 1是肿瘤治疗中一个新兴的、有前途的治疗靶点。本研究旨在探讨丹参酮IIA（TSA）的抗肿瘤作用是否依赖于NQO 1，并阐明其潜在的细胞凋亡途径。用NQO 1 + A549细胞和同基因匹配的转染NQO 1的阴性H596细胞检测TSA诱导细胞死亡的性质和机制。在肿瘤异种移植裸鼠中测试TSA的体内抗肿瘤功效和组织分布特性。我们观察到TSA在NQO 1 + A549细胞和H596-NQO 1细胞中诱导了过量的ROS产生、DNA损伤和显著的凋亡性细胞死亡，但在NQO 1 − H596细胞中没有。抑制或沉默NQO 1以及抗氧化剂NAC显着逆转TSA诱导的凋亡作用。TSA处理显著延缓A549肿瘤异种移植物的肿瘤生长，尽管TSA在肿瘤组织中积累增加和延长，但双香豆素共处理显著拮抗肿瘤生长。TSA激活ROS触发的、p53非依赖性和半胱天冬酶依赖性线粒体凋亡细胞死亡途径，其特征在于Bax与Bcl-xl的比率增加、线粒体膜电位破坏、细胞色素c释放和随后的半胱天冬酶激活和PARP-1裂解。这些发现的结果表明，TSA是一个高度特异性的NQO 1靶向剂，并有望发展为一种有效的药物，在治疗NQO 1阳性NSCLC。
NQO1 is an emerging and promising therapeutic target in cancer therapy. This study was to determine whether the anti-tumor effect of tanshinone IIA (TSA) is NQO1 dependent and to elucidate the underlying apoptotic cell death pathways. NQO1+ A549 cells and isogenically matched NQO1 transfected and negative H596 cells were used to test the properties and mechanisms of TSA induced cell death. The in vivo anti-tumor efficacy and the tissue distribution properties of TSA were tested in tumor xenografted nude mice. We observed that TSA induced an excessive generation of ROS, DNA damage, and dramatic apoptotic cell death in NQO1+ A549 cells and H596-NQO1 cells, but not in NQO1− H596 cells. Inhibition or silence of NQO1 as well as the antioxidant NAC markedly reversed TSA induced apoptotic effects. TSA treatment significantly retarded the tumor growth of A549 tumor xenografts, which was significantly antagonized by dicoumarol co-treatment in spite of the increased and prolonged TSA accumulations in tumor tissues. TSA activated a ROS triggered, p53 independent and caspase dependent mitochondria apoptotic cell death pathway that is characterized with increased ratio of Bax to Bcl-xl, mitochondrial membrane potential disruption, cytochrome c release, and subsequent caspase activation and PARP-1 cleavage. The results of these findings suggest that TSA is a highly specific NQO1 target agent and is promising in developing as an effective drug in the therapy of NQO1 positive NSCLC.
登录
查看更多内容
DOI：
10.1164/rccm.200305-684oc
发表时间：
2003-11-15
影响因子：
24.7
作者：
David, GL;Romieu, I;London, SJ
通讯作者：
London, SJ
影响因子：
3
作者：
Digby, T;Leith, MK;Begleiter, A
通讯作者：
Begleiter, A
影响因子：
7.4
作者：
Muller, Michael
通讯作者：
Muller, Michael
DOI：
10.1124/jpet.109.164608
发表时间：
2010-05-01
影响因子：
3.5
作者：
Noh, Ji-Yoon;Park, Jong-Sook;Chung, Jin-Ho
通讯作者：
Chung, Jin-Ho
影响因子：
3.7
作者：
Park, Moon-Taek;Song, Min-Jeong;Park, Heon Joo
通讯作者：
Park, Heon Joo