title: An NQO1-initiated and p53-independent apoptotic pathway determines the anti-tumor effect of tanshinone IIA against non-small cell lung cancer.
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.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors: Fang
authors: F
authors: Liu
authors: Guo
authors: G
authors: Yu
authors: Guangji
authors: G
authors: Wang
authors: Huiying
authors: H
authors: Liu
authors: Xiaolan
authors: X
authors: Wu
authors: Qiong
authors: Q
authors: Wang
authors: Miao
authors: M
authors: Liu
authors: Ke
authors: K
authors: Liao
authors: Mengqiu
authors: M
authors: Wu
authors: Xuefang
authors: X
authors: Cheng
authors: Haiping
authors: H
authors: Hao
mesh_terms: D045784:Abietanes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C021751:tanshinone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D020169:Caspases