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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.

Wu CC, Huang KF, Yang TY, Li YL, Wen CL, Hsu SL, Chen TH - PLoS ONE (2015)

Bottom Line: 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.These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC; Department of Medical Research, Chung-Shan Medical University Hospital, Taichung, Taiwan, ROC.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the anti-cancer mechanisms of austrobailignan-1 in human non-small cell lung cancer A549 and H1299 cell lines.
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pone.0132052.g007: Schematic representation of the anti-cancer mechanisms of austrobailignan-1 in human non-small cell lung cancer A549 and H1299 cell lines.

Mentions: Collectively, our observations provide evidence that austrobailignan-1, a lignan isolated from Koelreuteria henryi, was more potent than camptothecan in suppressing the topoisomerase 1 activity and inhibiting cell proliferation of human non-small cell lung cancer A549 and H1299 cells. Treatment of cells with austrobailignan-1 provoked a DNA damage response and induced the cell cycle arrest and apoptosis. Molecular and cellular mechanism studies revealed that austrabailignan-1 retarded cell cycle progression at G2/M phase through the ATM/Chks-Cdc25C, p21Cip1/Kip1 and p27Kip1 signaling pathways (Fig 7). Moreover, austrabailignan-1-induced apoptosis was via a Bcl-2 family protein-mediated mitochondrial death pathway (Fig 7). Besides, the relative lower working concentration of austrobailignan-1 compared with other traditional chemotherapeutic agents, such as cisplatin and doxorubicin (IC50 for A549 cells, cisplatin: 2–25 μM; doxorubicin: 2–5 μM, [75, 76]), makes it a potential chemotherapeutic candidate for the further study in the in vitro and in vivo models to determine the therapeutic efficacy and evaluate the potential of this compound for clinical applications.


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.

Wu CC, Huang KF, Yang TY, Li YL, Wen CL, Hsu SL, Chen TH - PLoS ONE (2015)

Schematic representation of the anti-cancer mechanisms of austrobailignan-1 in human non-small cell lung cancer A549 and H1299 cell lines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492957&req=5

pone.0132052.g007: Schematic representation of the anti-cancer mechanisms of austrobailignan-1 in human non-small cell lung cancer A549 and H1299 cell lines.
Mentions: Collectively, our observations provide evidence that austrobailignan-1, a lignan isolated from Koelreuteria henryi, was more potent than camptothecan in suppressing the topoisomerase 1 activity and inhibiting cell proliferation of human non-small cell lung cancer A549 and H1299 cells. Treatment of cells with austrobailignan-1 provoked a DNA damage response and induced the cell cycle arrest and apoptosis. Molecular and cellular mechanism studies revealed that austrabailignan-1 retarded cell cycle progression at G2/M phase through the ATM/Chks-Cdc25C, p21Cip1/Kip1 and p27Kip1 signaling pathways (Fig 7). Moreover, austrabailignan-1-induced apoptosis was via a Bcl-2 family protein-mediated mitochondrial death pathway (Fig 7). Besides, the relative lower working concentration of austrobailignan-1 compared with other traditional chemotherapeutic agents, such as cisplatin and doxorubicin (IC50 for A549 cells, cisplatin: 2–25 μM; doxorubicin: 2–5 μM, [75, 76]), makes it a potential chemotherapeutic candidate for the further study in the in vitro and in vivo models to determine the therapeutic efficacy and evaluate the potential of this compound for clinical applications.

Bottom Line: 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.These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC; Department of Medical Research, Chung-Shan Medical University Hospital, Taichung, Taiwan, ROC.

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.

No MeSH data available.


Related in: MedlinePlus