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
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Michelle S. Liberio1,2, Martin C. Sadowski1, Rohan A. Davis2, Anja Rockstroh1, Raj Vasireddy1, Melanie L. Lehman3, Colleen C. Nelson1
1Australian Prostate Cancer Research Centre – Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia
2Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia
3Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
Colleen Nelson, e-mail: [email protected]
Keywords: eusynstyelamide B, G2/M arrest, DNA damage, topoisomerase II poison, LNCaP
Received: July 26, 2015 Accepted: October 08, 2015 Published: November 02, 2015
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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