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Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells.


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Title: Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells.
Other Titles: DHMEQ, a novel NF-{kappa}B inhibitor, enhances anti-tumor activity of taxanes in anaplastic thyroid cancer cells (Author Manuscript title)
Authors: Meng, Zhaowei / Mitsutake, Norisato / Nakashima, Masahiro / Starenki, Dmytro / Matsuse, Michiko / Takakura, Shu / Namba, Hiroyuki / Saenko, Vladimir / Umezawa, Kazuo / Ohtsuru, Akira / Yamashita, Shunichi
Issue Date: Nov-2008
Publisher: The Endocrine Society
Citation: Endocrinology, 149(11), pp.5357-5365; 2008
Abstract: Nuclear factor kappaB (NF-kappaB), as an antiapoptotic factor, crucially affects the outcomes of cancer treatments, being one of the major culprits of resistance to chemotherapy. In this study, we investigated whether dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, can enhance antitumor activities of taxanes in anaplastic thyroid cancer (ATC) cells. Taxanes induced NF-kappaB activation in ATC cells, which could compromise the therapeutic effect of the drugs. However, DHMEQ, by inhibiting the nuclear translocation of NF-kappaB, completely suppressed the DNA binding capacities of NF-kappaB and lowered the levels of nuclear NF-kappaB protein. Compared with single treatment (either taxane or DHMEQ), the combined treatment strongly potentiated apoptosis, confirmed by cell survival assay; Western blotting for poly (ADP-ribose) polymerase, caspase 3, X-linked inhibitor of apoptosis, and survivin; and flow cytometry for annexin V. Furthermore, we also demonstrate for the first time that the combined treatment showed significantly greater inhibitory effect on tumor growth in a nude mice xenograft model. These findings suggest that taxanes are able to induce NF-kappaB activation in ATC cells, which could attenuate antitumor activities of the drugs, but inhibition of NF-kappaB by DHMEQ creates a chemosensitive environment and greatly enhances apoptosis in taxanes-treated ATC cells in vitro and in vivo. Thus, DHMEQ may emerge as an attractive therapeutic strategy to enhance the response to taxanes in ATCs.
Keywords: DHMEQ / NF-kappaB / paclitaxel / docetaxel / anaplastic thyroid cancer
URI: http://hdl.handle.net/10069/20193
ISSN: 00137227
DOI: 10.1210/en.2008-0279
PubMed ID: 18653704
Rights: Copyright © 2008 by The Endocrine Society
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/20193

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