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 2024-01-20T09:04:58Z 2024-01-20T09:04:58Z 2021-09-05 2014-08 1019-6439 https://pubs.kist.re.kr/handle/201004/126543 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 II alpha 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 Ha. In a biochemical assay, daurinol (10-100 mu M) inhibited the catalytic activity of topoisomerase Ha 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. English SPANDIDOS PUBL LTD ETOPOSIDE EXTENSION ENZYME Daurinol, a catalytic inhibitor of topoisomerase II alpha, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase Article 10.3892/ijo.2014.2442 1 INTERNATIONAL JOURNAL OF ONCOLOGY, v.45, no.2, pp.558 - 566 INTERNATIONAL JOURNAL OF ONCOLOGY 45 2 558 566 scie scopus 000338484600010 2-s2.0-84902583141 Oncology Oncology Article ETOPOSIDE EXTENSION ENZYME daurinol topoisomerase II alpha inhibitor ovarian cancer ATP binding pocket secondary leukemia