Dehydroxymethylepoxyquinomicin, a novel nuclear Factor-kappaB inhibitor, enhances antitumor activity of taxanes in anaplastic thyroid cancer cells.
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.
Meng
Zhaowei
Z
Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, Japan.
Mitsutake
Norisato
N
Nakashima
Masahiro
M
Starenki
Dmytro
D
Matsuse
Michiko
M
Takakura
Shu
S
Namba
Hiroyuki
H
Saenko
Vladimir
V
Umezawa
Kazuo
K
Ohtsuru
Akira
A
Yamashita
Shunichi
S
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
D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D043823:Taxoids; C464444:dehydroxymethylepoxyquinomicin