title: Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells.
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.
authors.affiliation: Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, Japan.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Meng
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Dmytro
authors.initials: D
authors.lastname: Starenki
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsuse
authors.forename: Shu
authors.initials: S
authors.lastname: Takakura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Namba
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saenko
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtsuru
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003512:Cyclohexanones / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D043823:Taxoids; C464444:dehydroxymethylepoxyquinomicin