The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells

Libério, Michelle S., Sadowski, Martin, Davis, Rohan, Rockstroh, Anja, Vasireddy, Raja S., Lehman, Melanie L., & Nelson, Colleen (2015) The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells. Oncotarget, 6(41), pp. 43944-43963.

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Abstract

As part of an anti-cancer natural product drug discovery program, we recently identified eusynstyelamide B (EB), which displayed cytotoxicity against MDA-MB-231 breast cancer cells (IC50 = 5 μM) and induced apoptosis. Here, we investigated the mechanism of action of EB in cancer cell lines of the prostate (LNCaP) and breast (MDA-MB-231). EB inhibited cell growth (IC50 = 5 μM) and induced a G2 cell cycle arrest, as shown by a significant increase in the G2/M cell population in the absence of elevated levels of the mitotic marker phospho-histone H3. In contrast to MDA-MB-231 cells, EB did not induce cell death in LNCaP cells when treated for up to 10 days. Transcript profiling and Ingenuity Pathway Analysis suggested that EB activated DNA damage pathways in LNCaP cells. Consistent with this, CHK2 phosphorylation was increased, p21CIP1/WAF1 was up-regulated and CDC2 expression strongly reduced by EB. Importantly, EB caused DNA double-strand breaks, yet did not directly interact with DNA. Analysis of topoisomerase II-mediated decatenation discovered that EB is a novel topoisomerase II poison.

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ID Code: 89515
Item Type: Journal Article
Refereed: Yes
Additional Information: This article has also featured in Mammary Cell News and Prostate Cell News (see Additional URLs below)
Additional URLs:
Keywords: Ascidian natural product, eusynstyelamide B, topoisomerase II poison, DNA damage, Growth arrest, prostate cancer, breast cancer, cancer therapy
DOI: 10.18632/oncotarget.6267
ISSN: 1949-2553
Subjects: Australian and New Zealand Standard Research Classification > CHEMICAL SCIENCE (030000) > ORGANIC CHEMISTRY (030500) > Natural Products Chemistry (030502)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Chemotherapy (111205)
Australian and New Zealand Standard Research Classification
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 The authors
Deposited On: 28 Oct 2015 23:59
Last Modified: 01 Jun 2016 00:05

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