A Novel Topoisomerase Inhibitor, Daurinol, Suppresses Growth of HCT116 Cells with Low Hematological Toxicity Compared to Etoposide

Autor: Kyungsu Kang, Seung Hyun Oh, Ji Ho Yun, Eun Hye Jho, Ju-Hee Kang, Dulamjav Batsuren, Jigjidsuren Tunsag, Kwang Hwa Park, Minkyun Kim, Chu Won Nho
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Neoplasia: An International Journal for Oncology Research, Vol 13, Iss 11, Pp 1043-1057 (2011)
Druh dokumentu: article
ISSN: 1476-5586
1522-8002
DOI: 10.1593/neo.11972
Popis: We report that daurinol, a novel arylnaphthalene lignan, is a promising potential anticancer agent with adverse effects that are less severe than those of etoposide, a clinical anticancer agent. Despite its potent antitumor activity, clinical use of etoposide is limited because of its adverse effects, including myelosuppression and the development of secondary leukemia. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation through the inhibition of DNA synthesis. Etoposide treatment induces G2/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic adverse effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIα, and it induces S-phase arrest through the enhanced expression of cyclins E and A and by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and adverse effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.
Databáze: Directory of Open Access Journals
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