Abstract
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.
Highlights
Non-small cell lung cancer (NSCLC) accounts for approximately 80,85% of all cases of lung cancer, and is the most common cause of death in men and second to breast cancer in women [1]
Accumulating evidence suggests that NQO1 is a promising therapeutic target for various tumors, especially for NSCLC, in which NQO1 is overexpressed compared with normal lung tissue [14]
Some anti-tumor drugs such as mitomycin can be bioactivated by NQO1, all of them lack sufficient selectivity and specificity to NQO1 and their anti-tumor effects are better explained by other mechanisms [38,39]
Summary
Non-small cell lung cancer (NSCLC) accounts for approximately 80,85% of all cases of lung cancer, and is the most common cause of death in men and second to breast cancer in women [1]. Combination chemotherapy, usually platinum-based, is currently the first-line therapy of choice for NSCLCs. the prognosis for patients with advanced NSCLC remains poor with a median survival time of 8 to months and a 1-year survival rate of 30% [2,3]. The long term survival (5-year) rate was even poor at around 15% [4]. The recent development of various molecular target drugs and their combination with chemotherapy drugs improves the outcome of NSCLC therapy; it remains disappointing in the therapy of advanced NSCLC.
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