Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

Kang,Kyungsu; Nho,Chu Won; Kim,Nam Doo; Song,Dae-Geun; Park,Young Gyun; Kim,Minkyun; Pan,Cheol-Ho; Shin,Dongyun; Oh,Seung Hyun; Oh,Ho-Suk

doi:10.3892/ijo.2014.2442

August-2014 Volume 45 Issue 2

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August-2014 Volume 45 Issue 2

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Article

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

Authors:
- Kyungsu Kang
- Chu Won Nho
- Nam Doo Kim
- Dae-Geun Song
- Young Gyun Park
- Minkyun Kim
- Cheol-Ho Pan
- Dongyun Shin
- Seung Hyun Oh
- Ho-Suk Oh
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Affiliations: Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea, New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea, College of Pharmacy, Gachon University, Incheon, Republic of Korea, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea
Pages: 558-566
|
Published online on: May 16, 2014

https://doi.org/10.3892/ijo.2014.2442
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Abstract

Daurinol, a lignan from the ethnopharmacological plant Haplophyllum dauricum, was recently reported to be a novel topoisomerase II inhibitor and an alternative to the clinical anticancer agent etoposide based on a colorectal cancer model. In the present study, we elucidated the detailed biochemical mechanism underlying the inhibition of human topoisomerase IIα by daurinol based on a molecular docking study and in vitro biochemical experiments. The computational simulation predicted that daurinol binds to the ATP-binding pocket of topoisomerase IIα. In a biochemical assay, daurinol (10-100 µM) inhibited the catalytic activity of topoisomerase IIα in an ATP concentration-dependent manner and suppressed the ATP hydrolysis activity of the enzyme. However, daurinol did not inhibit topoisomerase I activity, most likely because topoisomerase I does not contain an ATP-binding domain. We also evaluated the anti-proliferative activity of daurinol in ovarian, small cell lung and testicular cancer cells, common target cancers treated with etoposide. Daurinol potently inhibited SNU-840 human ovarian cancer cell proliferation through cell cycle arrest in S phase, while etoposide induced G2/M phase arrest. Daurinol induced the increased expression of cyclin E, cyclin A and E2F-1, which are important proteins regulating S phase initiation and progression. Daurinol did not induce abnormal cell and nuclear enlargement in SNU-840 cells, in contrast to etoposide. Based on these data, we suggest that daurinol is a potential anticancer drug candidate for the treatment of human ovarian cancer with few side effects.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

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