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RISS 인기검색어
- 검색키워드
- 저자 : Kazuo Umezawa (검색결과 3 건)
- 무료
- 기관 내 무료
- 유료
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Molecular design and biological activities of NF-ĸB and protein-tyrosine phosphatase inhibitors
Kazuo Umezawa 이화여자대학교 세포신호전달연구센터 2002 고사리 세포신호전달 심포지움 Vol. No.4
NF-ĸB is a transcription factor that mediates the expression of a variety of cellular genes regulating inflammation, immune responses, and sensitivity to apoptosis. NF-ĸB is constitutively activated in various human carcinomas. Therefore, NF-ĸB inhibitors may be developed into new cancer chemotherapeutic agents. Recently, we designed and synthesized a dehydroxymethyl derivative of epoxyquinomicin C(DHMEQ) as an NF-ĸB function inhibitor(Bioorg. Med. Chem. Lett. 10, 865-869, 2000). We tested the effect of DHMEQ on TNF-α-induced NF-ĸB activation in human T cell leukemia Jurkat cells. In a DNA mobility shift assay DHMEQ inhibited the binding of nuclear NF-ĸB to ĸB DNA. On the other hand, DHMEQ did not inhibit TNF-α-induced phosphorylation and degradation of I-ㅏB as judged from the results of West em blotting analysis. DHMEQ also inhibited the translocation of NF-kB from the cytoplasm to the nucleus. DHMEQ increased the sensitivity of Jurkat cells to apoptosis, and showed an anti-arthritic effect in mice. It also showed antitumor activity in mice. To develop new chemotherapeutic agents for type 2 diabetes mellitus we designed and synthesized protein-tyrosine phosphatase(PTPase) inhibitors. We previously isolated dephostatin from Streptomyces as a novel inhibitor of CD45-associated PTPase(J. Antibiot. 46, 1342-1346, 1993). We prepared its stable analogue, Et-3,4-dephostatin, and found it to specifically inhibit PTP-1B which is known to negatively regulate insulin activities. Et-3,4-dephostatin increased tyrosine phosphorylation of insulin receptors and IRS-1 in 3T3-L1 adipocytes. Et-3,4-dephostatin enhanced translocation of GLUT4 from the cytoplasm to the plasma membrane and 2-deoxyglucose transport(J. Biol. Chem. 276, 27511-27518, 2001). We further designed nitrosamine-free analogues by calculation employing the software for CH/π interaction. As a result, methoxime-3,4-dephostatin having no nitrosamine was found to inhibit PTP-1B effectively(Tetrahedron 56, 741-752, 2000). Et-3,4-dephostatin and methoxime-3,4-dephostatin showed antidiabetic effect in vivo by oral administartion.
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Molecular Design and Biological Activities of NF-kB Inhibitors
Kazuo Umezawa,Chanya Chaicharoenpong 한국분자세포생물학회 2002 Molecules and cells Vol.14 No.2
NF-kB is a transcription factor that induces inflamma-tory cytokines and anti-apoptotic proteins. We de-signed a new NF-kB inhibitor that is based on the structure of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquino-micin (DHMEQ), inhibited the TNF-a-induced activa-tion of NF-kB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibi-tion. DHMEQ inhibited the TNF-a-induced cellular DNA binding of nuclear NF-kB, but not the phos-phorylation or degradation of I-kB. Moreover, DHMEQ inhibited the TNF-a-induced nuclear accu-mulation of p65, a component of NF-kB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-a-induced activation of JNK, but synergisti-cally induced apoptosis with TNF-a in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-kB-activating pathway in the TNF-a-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-kB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.
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Cytostatic in vitro Effects of DTCM-Glutarimide on Bladder Carcinoma Cells
Brassesco, Maria S.,Pezuk, Julia A.,Morales, Andressa G.,De Oliveira, Jaqueline C.,Valera, Elvis T.,Da Silva, Glenda N.,De Oliveira, Harley F.,Scrideli, Carlos A.,Umezawa, Kazuo,Tone, Luiz G. Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.5
Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 ${\mu}g/ml$ DTCM-glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.
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