MP-12.10

Horiguchi, Yutaka; Kosugi, Michio; Kikuchi, Eiji; Miyajima, Asami; Nakashima, Jun-ichi; Murai, Makoto; Umezawa, Kazuo; Tachibana, Maki

doi:10.1016/j.urology.2006.08.415

Cited by 1 publication

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“…This drug promotes apoptosis in various cancer cell types and has been shown to be effective against rheumatoid arthritis, bladder cancer, and hormonerefractory prostate cancer in an in vivo model without apparent toxic side effects (13,14). The present study was set up to determine the effects of DHMEQ in thyroid carcinoma cells both in vitro and in vivo and to additionally elucidate the molecular mechanisms underlying the action of this chemotherapeutic agent.…”

Section: Introductionmentioning

confidence: 99%

Induction of Thyroid Cancer Cell Apoptosis by a Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin

Starenki¹,

Namba²,

Saenko

et al. 2004

Clinical Cancer Research

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Purpose: The objective of the study was to determine the effects of a novel selective nuclear factor B (NF-B) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in thyroid carcinoma cells in vitro and in vivo and to additionally elucidate the molecular mechanisms underlying the action of this chemotherapeutic agent.Experimental Design: In the in vitro experiments, the induction of apoptosis by DHMEQ in various human thyroid carcinoma cell types was determined by flow cytometry analysis of annexin-V binding and the caspase activation by Western blotting. For the in vivo study, female nu/nu mice were xenografted with s.c. FRO thyroid tumors. DHMEQ solution was injected i.p. at a dose of 8 mg/kg/day for two weeks. Tumor dimensions were monitored twice weekly, and apoptosis in tumor specimens was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling staining.Results: Treatment with DHMEQ substantially inhibited the translocation of p65 and p50 NF-B subunits to the nucleus, the DNA-binding activity of the RelA/p65, NF-Bdependent expression of the inhibitor of apoptosis (IAP)-family proteins, cIAP-1, cIAP-2, and XIAP, and the de novo synthesis of inhibitor of nuclear factor B ␣. At concentration levels ranging from 0.1 to 5 g/ml, DHMEQ induced a caspase-mediated apoptotic response that could be abrogated by the c-Jun NH 2 -terminal kinase inhibitor SP600125 but not by either mitogen-activated protein/extracellular signal-regulated kinase kinase or p38 inhibitors. In contrast, normal human thyrocytes were resistant to DHMEQinduced apoptosis. At higher doses of DHMEQ we observed the necrotic-like killing of both normal and malignant thyrocytes, which was resistant to mitogen-activated protein kinase inhibitors. In nude mice DHMEQ substantially inhibited tumor growth without observable side effects, and increased numbers of apoptotic cells were observed in the histologic sections of tumors treated with DHMEQ.Conclusions: Our results show the potential usefulness of the novel NF-B inhibitor, DHMEQ, in future therapeutic strategies for the treatment of thyroid cancers that do not respond to conventional approaches.

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Section: Introductionmentioning

confidence: 99%