TY - JOUR
T1 - Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells
AU - Meng, Zhaowei
AU - Mitsutake, Norisato
AU - Nakashima, Masahiro
AU - Starenki, Dmytro
AU - Matsuse, Michiko
AU - Takakura, Shu
AU - Namba, Hiroyuki
AU - Saenko, Vladimir
AU - Umezawa, Kazuo
AU - Ohtsuru, Akira
AU - Yamashita, Shunichi
PY - 2008/11
Y1 - 2008/11
N2 - Nuclear factor κB (NF-κB), 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-κB inhibitor, can enhance antitumor activities of taxanes in anaplastic thyroid cancer (ATC) cells. Taxanes induced NF-κB activation in ATC cells, which could compromise the therapeutic effect of the drugs. However, DHMEQ, by inhibiting the nuclear translocation of NF-κB, completely suppressed the DNA binding capacities of NF-κB and lowered the levels of nuclear NF-κB protein. Compared with single treatment (either taxane or DHMEQ), the combined treatment strongly potentiated apoptosis, confirmed by cell survival assay; Western blotting for poly (ADPribose) 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-κB activation in ATC cells, which could attenuate antitumor activities of the drugs, but inhibition of NF-κB 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.
AB - Nuclear factor κB (NF-κB), 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-κB inhibitor, can enhance antitumor activities of taxanes in anaplastic thyroid cancer (ATC) cells. Taxanes induced NF-κB activation in ATC cells, which could compromise the therapeutic effect of the drugs. However, DHMEQ, by inhibiting the nuclear translocation of NF-κB, completely suppressed the DNA binding capacities of NF-κB and lowered the levels of nuclear NF-κB protein. Compared with single treatment (either taxane or DHMEQ), the combined treatment strongly potentiated apoptosis, confirmed by cell survival assay; Western blotting for poly (ADPribose) 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-κB activation in ATC cells, which could attenuate antitumor activities of the drugs, but inhibition of NF-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=54349105133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54349105133&partnerID=8YFLogxK
U2 - 10.1210/en.2008-0279
DO - 10.1210/en.2008-0279
M3 - Article
C2 - 18653704
AN - SCOPUS:54349105133
VL - 149
SP - 5357
EP - 5365
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 11
ER -