Mechanisms underlying therapeutic effect of a new compound Isorhapontigenin (ISO)

新化合物Isorhapontigenin (ISO)的治疗作用机制

• 批准号: 8555171
• 负责人: CHUANSHU HUANG
• 金额: $ 35.17万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555171
• 关键词: Actins; Affect; Apoptosis; Attenuated; Binding; Binding Sites; Bladder Neoplasm; Bladder Tissue; Butylhydroxybutylnitrosamine; Carcinogens; Cell Cycle; Cell Line; Cell Proliferation; Cells; Cessation of life; China; Chinese Herbs; Chinese People; Clinical; Clinical Trials; Data; Development; Disease; Dose; Down-Regulation; Ectopic Expression; Frequencies; Genetic Transcription; Gnetum; Goals; Grant; Health; Human; In Vitro; Life; Lung; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Molecular; Molecular Conformation; Mus; Neoplasm Metastasis; Nude Mice; Oncogenic; Outcome; Papillary; Pathway interactions; Patients; Plants; Point Mutation; Promoter Regions; Protein Overexpression; Regulation; Resistance; Role; SP1 gene; Stilbenes; Testing; Therapeutic Agents; Therapeutic Effect; Tissues; Transactivation; Validation; Western World; Wild Type Mouse; Work; attenuation; base; bladder transitional cell carcinoma; cancer cell; cell motility; chemical carcinogen; design; human BIRC4 protein; improved; in vivo; inhibitor-of-apoptosis protein; migration; mortality; mouse model; novel; polymerization; protein expression; rhoB p20 GDI; success; vector

DESCRIPTION (provided by applicant): Urothelial carcinoma of the bladder (or bladder cancer, BC) is one of the most common cancers in the Western world. Because high-grade invasive bladder cancers (HGIBC) can progress to life threatening metastases, identifying a natural compound that specifically inhibits BC invasion and metastasis is of tremendous importance for potentially reducing mortality as a result of this disease. Isorhapontigenin (ISO) i a new derivative of stilbene, and isolated from a Chinese herb that has been used in China for treatment of BCs for hundreds of years without understanding of molecular mechanisms. Thus, the goal of this proposal is to determine the ISO potential therapeutic effect and the molecular mechanisms responsible for this anti-cancer activity. Our preliminary studies found that the X-linked inhibitor of the apoptosis protein (XIAP) was extremely highly expressed in all of the human invasive BC tissues that were tested, but it was barely detectable in all adjacent normal bladder tissues, and that XIAP expression level was also markedly elevated in BBN-induced invasive BC tissues in p53-/-/pRb-/- mice as compared with that from wild-type mice and oncogenic Ras- induced low-grade BCs. We also found that XIAP was significantly higher in cultured human BC cells derived from HGIBC than from those derived from low-grade papillary bladder tumors (LGPBT). Moreover, we showed that treatment of BC cells with ISO inhibited HGIBC T24T cell migration and invasion, was accompanied with specific inhibition of Sp-1 transactivation and XIAP downregulation at the transcription level without affecting cell proliferation at doses of 5-10 ¿M. Thus, we hypothesize that ISO is an effective therapeutic agent for the inhibition of BC invasion in vitro and BC invasion and metastasis in vivo via downregulation of the Sp-1/XIAP pathway. We will test this with the following aims: 1: To test the hypothesis that XIAP downregulation by ISO is responsible for its inhibition of BBN-induced BC formation in the mice lacking both p53 and pRb; 2: To evaluate the hypothesis that SP-1 is a major target for ISO downregulation of XIAP in BC in vitro and in vivo; 3: To define the molecular mechanisms whereby ISO inhibits the BC development in vitro and in vivo. Success of the proposal will facilitate our understanding of the molecular mechanism(s) responsible for the anti-cancer effects of ISO compound. This novel finding will provide valuable information for the design of more effective strategies for utilization of ISO or for the synthesis of other novel conformation- constrained derivatives for the treatment of BCs and other cancers. Taken together with the fact that BC is the most common malignant tumors, responsible for 336,000 new cases and 132,000 deaths annually worldwide, the studies should in turn help improve the clinical outcome of patients with BCs.

描述（由适用提供）：膀胱（或bladeder癌，卑诗省）的尿路上皮癌是西方世界上最常见的癌症之一。由于高级侵入性膀胱癌（HGIBC）可以发展到威胁生命转移酶的情况，因此确定一种天然化合物，特异性地抑制BC侵袭和转移对于由于这种疾病而导致死亡率的潜在死亡率至关重要。异甲替尼蛋白（ISO）I是Stilbene的新衍生物，并从中国用于治疗BCS的中国草药中分离了数百年，而无需了解分子机制。这是该提案的目的是确定ISO潜在的治疗效应和造成这种抗癌活性的分子机制。 Our preliminary studies found that the X-linked inhibitor of the apoptosis protein (XIAP) was extremely highly expressed in all of the human invasive BC tissues That were tested, but it was barely detectable in all adjacent normal bladeder tissues, and that XIAP expression level was also markedly elevated in BBN-induced invasive BC tissues in p53-/-/pRb-/- mice as compared with that来自野生型小鼠和致癌性RAS诱导的低度BC。我们还发现，源自HGIBC的培养的人类BC细胞的XIAP明显高于低级乳头状膀胱肿瘤（LGPBT）的XIAP。此外，我们表明，用ISO抑制的HGIBC T24T细胞迁移和入侵对BC细胞的处理是通过特异性抑制在转录水平上的SP-1反式激活和XIAP下调的特异性来完成的，而在5-10的剂量下，在5-10的剂量下，我们可以通过5-10的剂量增殖。通过下调SP-1/XIAP途径的体内。我们将以以下目的进行测试：1：测试ISO的XIAP下调的假设负责抑制其在缺乏p53和PRB的小鼠中BBN诱导的BC形成； 2：评估SP-1是BC体外和体内XIAP的ISO下调的主要目标的假设； 3：定义ISO在体外和体内抑制BC发育的分子机制。该提案的成功将促进我们对负责ISO化合物抗癌作用的分子机制的理解。这一新颖的发现将为设计ISO的更有效策略或其他新型构象控制的衍生物用于治疗BC和其他癌症的其他新型策略提供有价值的信息。鉴于卑诗省是最常见的恶性肿瘤，每年在全球范围内导致336,000例新病例和132,000例死亡，而研究应有助于改善BCS患者的临床结果。