Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase.
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 topo-isomerase 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.
Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.
Kyungsu
K
Kang
Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.
Chu Won
CW
Nho
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
Nam Doo
ND
Kim
Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.
Dae-Geun
DG
Song
Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.
Young Gyun
YG
Park
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
Minkyun
M
Kim
Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.
Cheol-Ho
CH
Pan
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
Dongyun
D
Shin
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
Seung Hyun
SH
Oh
Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea.
Ho-Suk
HS
Oh
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D016196:S Phase / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; D004268:DNA-Binding Proteins; D009281:Naphthalenes; D059005:Topoisomerase II Inhibitors; C571067:daurinol; D004250:DNA Topoisomerases, Type II