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: 8688975
• 负责人: CHUANSHU HUANG
• 金额: $ 34.12万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688975
• 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（由申请人提供）：膀胱尿路上皮癌（或膀胱癌，BC）是西方世界最常见的癌症之一，因为高级别浸润性膀胱癌（HGIBC）可进展为危及生命的转移，因此需要确定一种癌症。特异性抑制 BC 侵袭和转移的天然化合物对于降低这种疾病导致的死亡率具有极其重要的意义，异硫皂苷元 (ISO) 是一种二苯乙烯的新衍生物，已被分离出来。来自一种在中国用于治疗乳腺癌数百年的中草药，但对其分子机制尚无了解。因此，本提案的目标是确定 ISO 的潜在治疗效果以及导致这种抗癌活性的分子机制。我们的初步研究发现，X连锁凋亡蛋白抑制剂（XIAP）在所有测试的人类侵袭性BC组织中均极高表达，但在所有邻近的正常膀胱组织中几乎检测不到，并且XIAP表达水平也显着升高与野生型小鼠和致癌 Ras 诱导的低级 BC 相比，p53-/-/pRb-/- 小鼠中 BBN 诱导的侵袭性 BC 组织我们还发现，在培养的人 BC 细胞中，XIAP 显着较高。此外，我们发现用 ISO 处理 BC 细胞可抑制 HGIBC T24T 细胞迁移和侵袭，同时还特异性抑制 HGIBC 细胞的迁移和侵袭。 Sp-1 反式激活和 XIAP 在转录水平下调，在 5-10 ¿ 剂量下不影响细胞增殖M. 因此，我们追求 ISO 是一种通过下调 Sp-1/XIAP 途径来抑制体外 BC 侵袭和体内 BC 侵袭和转移的有效治疗剂，我们将通过以下目标进行测试：1：检验 ISO 下调 XIAP 抑制缺乏 p53 和 pRb 的小鼠中 BBN 诱导的 BC 形成的假设；2：评估 SP-1 是 ISO 下调 XIAP 的主要靶标的假设； BC 体外和体内；3：明确 ISO 抑制体外和体内 BC 发展的分子机制。该提案的成功将有助于我们了解 ISO 抗癌作用的分子机制。这一新发现将为设计更有效的利用 ISO 的策略或合成用于治疗 BC 和其他癌症的其他新型构象限制衍生物提供有价值的信息。常见的恶性肿瘤，负责全球每年有 336,000 例新病例和 132,000 例死亡，这些研究反过来应该有助于改善 BC 患者的临床结果。