An NQO1-Initiated and p53-Independent Apoptotic Pathway Determines the Anti-Tumor Effect of Tanshinone IIA against Non-Small Cell Lung Cancer
Open Access
- 27 July 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (7), e42138
- https://doi.org/10.1371/journal.pone.0042138
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.Keywords
This publication has 52 references indexed in Scilit:
- Tanshinone IIA: A Promising Natural Cardioprotective AgentEvidence-Based Complementary and Alternative Medicine, 2012
- β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer CellsPLOS ONE, 2011
- A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated ErythrophagocytosisThe Journal of pharmacology and experimental therapeutics, 2010
- Sodium Tanshinone IIA Sulfonate Protects Cardiomyocytes Against Oxidative Stress-mediated Apoptosis Through Inhibiting JNK ActivationJournal of Cardiovascular Pharmacology, 2008
- Systemic Chemotherapy for Advanced Non‐Small Cell Lung Cancer: Recent Advances and Future DirectionsThe Oncologist, 2008
- An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by β-lapachoneProceedings of the National Academy of Sciences of the United States of America, 2007
- Pharmacokinetics, Absorption and Tissue Distribution of Tanshinone IIA Solid DispersionPlanta Medica, 2006
- Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancerEuropean Journal of Cancer, 2005
- RETRACTION: 5-aza-Cytidine Is a Potent Inhibitor of DNA Methyltransferase 3a and Induces Apoptosis in HCT-116 Colon Cancer Cells via Gadd45- and p53-Dependent MechanismsJournal of Pharmacology and Experimental Therapeutics, 2004
- Development, pharmacology, role of DT-diaphorase and prospects of the indoloquinone EO9General Pharmacology: The Vascular System, 1996