| Title | Tanshinone IIA triggers p53 responses and apoptosis by RNA polymerase II upon DNA minor groove binding |
| Authors | Zhang, Zhichao Gao, Jin Wang, Yuanyuan Song, Ting Zhang, Jing Wu, Guiye Zhang, Tiantai Du, Guanhua |
| Affiliation | Dalian Univ Technol, State Key Lab Fine Chem, Dalian 116012, Peoples R China. Dalian Univ Technol, Sch Environm & Biol Sci & Technol, Dalian 116024, Peoples R China. Xinao Res Inst, Genet Engn Div, Langfang, Peoples R China. Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. Chinese Acad Med Sci, Natl Ctr Drug Screening, Inst Mat Med, Beijing 100050, Peoples R China. Peking Union Med Coll, Beijing 100050, Peoples R China. 158-89 Zhongshan Rd, Dalian 116012, Peoples R China. |
| Keywords | Tanshinone IIA DNA minor groove binder RNA polymerase II Apoptosis SALVIA-MILTIORRHIZA CELL-LINES TRANSCRIPTION PHOSPHORYLATION CYTOTOXICITY MECHANISMS ARREST CANCER |
| Issue Date | 2009 |
| Publisher | biochemical pharmacology |
| Citation | BIOCHEMICAL PHARMACOLOGY.2009,78,(10),1316-1322. |
| Abstract | Our previous work has shown that tainshinone IIA (Tan IIA) is a DNA minor groove binder instead of an intercalator as previously thought. In this study, we have further demonstrated that the molecular antitumor pharmacology of Tan IIA is dependent on its groove-binding capability. First,we investigated the structure damage to duplex DNA upon Tan IIA binding using circular dichroism spectra. Subsequently, we performed western blot, flow cytometry analysis, chromatin immunoprecipitation, and quantitative real-time PCR to illustrate the RNAPII degradation, phosphorylation, and distribution along the transcribed gene in H22 cells exposed to Tan IIA. In addition, p53 activation and apoptosis induction in both cultured H22 cells and in mice bearing the ascitic-type H22 were measured following Tan IIA treatment. It was revealed that Tan IIA decreases the level of RNAPII by altering DNA structure. At the low dose range (0.2-4 mu M) of Tan IIA exposure, the DNA structure damage results in the inhibition of RNAPH binding to DNA and the initiation of RNAPII phosphorylation, while higher concentrations of Tan IIA (4-20 mu M) cause complete phosphorylation and degradation of RNAPII followed by p53 activation and apoptosis. A similar apoptosis induction by RNAPII was observed in animals. Apoptosis of tumor cells from ascitic fluid was not detected until RNAPII levels were downregulated by Tan IIA, which requires 40 mg/kg body weight of Tan IIA It was concluded that DNA-conformational-damage-dependent RNAPII response upon groove binding is the molecular basis of the antitumor property of Tan IIA, in vivo and in vitro. (C) 2009 Elsevier Inc. All rights reserved. |
| URI | http://hdl.handle.net/20.500.11897/245133 |
| ISSN | 0006-2952 |
| DOI | 10.1016/j.bcp.2009.06.110 |
| Indexed | SCI(E) |
| Appears in Collections: | 天然药物与仿生药物国家重点实验室 |
