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Pathophysiological role of NF k B and the efficacy of a novel NF K B inhibitor in urological cancers

NF k B 的病理生理学作用以及新型 NF k B 抑制剂在泌尿系统癌症中的功效

基本信息

批准号：
16390469
负责人：
MURAI Masaru
金额：
$ 8.64万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390469/
关键词：
NF-κB urological malignancy apoptosis metastasis cytokine 前立腺癌放射線治療細胞周期 IL-6 STAT3 膀胱癌殺細胞効果

项目摘要

NF-κB is a transcription factor consisting mainly of p65 and p50 proteins and induces inflammatory cytokines and anti-apoptotic proteins. Activation of NF-κB is associated with apoptotic resistance, angiogenesis, and carcinogenesis by its fundamental implication in cellular dedifferentiation and proliferation. It is also possible that NF-κB is involved in the pathophysiology of urological malignancies including a variety of mechanisms of oncogenesis, invasion and metastases, chemoresistance, radioresistance, cachexia and so on. Therefore, an inhibitor of NF-κB function is expected to work as an anti-cancer agent. We have newly synthesized a dehydroxymethyl derivative of epoxyquinomicin named DHMEQ from a natural product, which is a novel and strong NF-KB inhibitor. NF-κB is constitutively activated in hormone-refractory prostate cancer and invasive bladder cancer cells. DHMEQ inhibited NF-κB activity resulting in the induction of apoptosis in hormone-refractory prostate cancer in vitro … More and in vivo. Inducible activation of NF-κB is one of the principal mechanism in which resistant prostate cancer cells are protected from radiotherapy. Pretreatment with DHMEQ significantly enhanced the inhibitory effect of irradiation through cell cycle G2/M arrest against prostate cancer cells. Furthermore, DHMEQ produced a significant decrease of cell viability and tumor growth of KU-19-19 cells, a cytokine-producing bladder cancer cell line by inducing apoptosis and inhibiting angiogenesis. DHMEQ inhibited lung metastases in metastatic model of bladder tumor using MBT-2 cells. CPT-11 in combination with DHMEQ demonstrated synergistic cytotoxic effects against several bladder cancer cell lines. Based on these encouraging data, DHMEQ possibly exerted its suppressive effect on hormone refractory prostate cancer and invasive bladder cancer in which NF-κB is constitutively activated. Serum levels of IL-6, which is an NF-κB dependent cytokine, were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. Serum IL-6 levels were significantly associated with serum total protein and albumin levels, serum total cholesterol levels, hemoglobin levels, body mass index, performance status and the survival in patients with prostate cancer. Therefore, IL-6 may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer. DHMEQ prevented the development of cachexia through the inhibition of IL-6 secretion in an animal model. Blockade of NF-κB function by DHMEQ could be a novel and unique molecular targeting anti-cancer strategy against aggressive urological malignancies. Less

NF-κB是一种主要由p65和p50蛋白组成的转录因子，并诱导炎性细胞因子和抗凋亡蛋白。NF-κB的活化与细胞凋亡抗性、血管生成和癌发生有关，其基本含义是细胞去分化和增殖。NF-κB还可能参与泌尿系恶性肿瘤的发生、侵袭和转移、化疗耐药、放射耐药、恶病质等多种病理生理过程，因此NF-κB功能抑制剂有望成为一种抗肿瘤药物。我们从天然产物中合成了一个新的去羟甲基环氧喹诺霉素衍生物DHMEQ，它是一种新型的强NF-κ B抑制剂。NF-κB在难治性前列腺癌和浸润性膀胱癌细胞中被组成性激活。DHMEQ抑制NF-κB活性诱导前列腺癌细胞凋亡 ...更多信息和体内。NF-κB的诱导性激活是抵抗性前列腺癌细胞免受放射治疗的主要机制之一。DHMEQ预处理可显著增强照射对前列腺癌细胞的G2/M期阻滞抑制作用。此外，DHMEQ通过诱导细胞凋亡和抑制血管生成而显著降低了KU-19-19细胞的细胞活力和肿瘤生长，KU-19-19细胞是一种产生嘌呤的膀胱癌细胞系。DHMEQ抑制MBT-2膀胱肿瘤转移模型肺转移。CPT-11与DHMEQ组合显示出对几种膀胱癌细胞系的协同细胞毒性作用。基于这些令人鼓舞的数据，DHMEQ可能发挥其对激素难治性前列腺癌和浸润性膀胱癌的抑制作用，其中NF-κB是组成性激活的。IL-6（一种NF-κB依赖性细胞因子）的血清水平显著升高，并且在JCA-1荷瘤小鼠以及疾病进展的前列腺癌患者中出现恶病质。血清IL-6水平与前列腺癌患者的血清总蛋白、白蛋白、血清总胆固醇、血红蛋白、体重指数、体力状态及生存期显著相关。因此，IL-6可能是导致前列腺癌患者恶病质综合征的因素之一。在动物模型中，DHMEQ通过抑制IL-6分泌来防止恶病质的发展。DHMEQ阻断NF-κB功能可能是一种新的、独特的分子靶向抗癌策略。少

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells

DOI：
10.1002/pros.20117
发表时间：
2005-01-01
期刊：
PROSTATE
影响因子：
2.8
作者：
Ohigashi, T;Mizuno, R;Murai, M
通讯作者：
Murai, M

Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in prostate cancer

血管紧张素 II 1 型受体拮抗剂作为前列腺癌的血管生成抑制剂

DOI：
发表时间：
2007
期刊：
Prostate 67
影响因子：
0
作者：
Kosaka T;Miyajima A;Takayama E;Kikuchi E;Nakashima J;Ohigashi T;Asano T;Sakamoto M;Okita H;Murai M;Hayakawa M
通讯作者：
Hayakawa M

Interleukin 6 is associated with cachexia in patients with prostate cancer