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| ITanshinone IIA (TSA) has been well defined a promising anti-cancer compound; however, its intracellular target remains unclear. Based on our previous finding that the NAD(P)H:quinone oxidoreductase (NQO1) reduced TSA to form a highly unstable catechol intermediate which auto-oxidized back to TSA, we hypothesized herein that NQO1 was the potential intracellular target of TSA to elicit its anti-tumor activity. In a pair of non-small-cell lung cancer cell lines, we found TSA exhibited a potent cytotoxic and apoptotic effect in NQO1+ A549 cells, but not in NQO1- H596 cells. In contrast, TSA exhibited efficient and almost identical uptake in A549 and H596 cells. Dicoumarol (DIC), a specific inhibitor of NQO1, could reverse largely the cytotoxic and apoptotic effect of TSA in A549 cells. TSA induced an excessive generation of reactive oxygen species, DNA damage, and G0/G1 phase arrest in A549 cells, whereas very little of such effects were observed in H596 cells and DIC pretreated A549 cells. N-acetyl cysteine also abolished almost all test aspects of TSA induced cytotoxic effects. TSA induced apoptotic cell death seemed to be p53 independent, because pifithrin-α pretreatment exerted little influence on TSA induced apoptosis and cytotoxcity, and TSA synergized DIC effect on decreasing p53 protein level. In conclusion, the present study suggests that NQO1 is likely the intracellular target of TSA, and that the NQO1 catalyzed futile redox cycle leading to the generation of ROS plays a pivotal role on TSA induced apoptotic and cytotoxic effects in NSCLC cells. |
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| Keywords:ktanshinone IIA; non-small-cell lung cancer; NQO1; apoptosis; ROS |
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