The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells.

Abstract

Koelreuteria henryi Dummer, an endemic plant of Taiwan, has been used as a folk medicine for the treatment of hepatitis, enteritis, cough, pharyngitis, allergy, hypertension, hyperlipidemia, and cancer. Austrobailignan-1, a natural lignan derivative isolated from Koelreuteria henryi Dummer, has anti-oxidative and anti-cancer properties. However, the effects of austrobailignan-1 on human cancer cells have not been studied yet. Here, we showed that austrobailignan-1 inhibited cell growth of human non-small cell lung cancer A549 and H1299 cell lines in both dose- and time-dependent manners, the IC50 value (48 h) of austrobailignan-1 were 41 and 22 nM, respectively. Data from flow cytometric analysis indicated that treatment with austrobailignan-1 for 24 h retarded the cell cycle at the G2/M phase. The molecular event of austrobailignan-1-mediated G2/M phase arrest was associated with the increase of p21Waf1/Cip1 and p27Kip1 expression, and decrease of Cdc25C expression. Moreover, treatment with 100 nM austrobailignan-1 for 48 h resulted in a pronounced release of cytochrome c followed by the activation of caspase-2, -3, and -9, and consequently induced apoptosis. These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2. Furthermore, our study also showed that austrobailignan-1 was a topoisomerase 1 inhibitor, as evidenced by a relaxation assay and induction of a DNA damage response signaling pathway, including ATM, and Chk1, Chk2, γH2AX phosphorylated activation. Overall, our results suggest that austrobailignan-1 is a novel DNA damaging agent and displays a topoisomerase I inhibitory activity, causes DNA strand breaks, and consequently induces DNA damage response signaling for cell cycle G2/M arrest and apoptosis in a p53 independent manner.

• Authors: Chun-Chi Wu, Keh-Feng Huang, Tsung-Ying Yang, Ya-Ling Li, Chi-Luan Wen, Shih-Lan Hsu, Tzu-Hsiu Chen
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0132052 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26147394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lignans
• TP53 protein, human
• Topoisomerase I Inhibitors
• Tumor Suppressor Protein p53
• austrobailignan 1
• DNA Topoisomerases, Type I

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• DNA Topoisomerases, Type I (metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Lignans (chemistry, pharmacology)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• M Phase Cell Cycle Checkpoints (drug effects)
• Plants, Medicinal (chemistry)
• Topoisomerase I Inhibitors (chemistry, pharmacology)
• Tumor Suppressor Protein p53 (metabolism)