iNOS/Akt Inhibotor for Colon Cancer Chemoprevention

用于结肠癌化学预防的 iNOS/Akt 抑制剂

• 批准号: 7590100
• 负责人: Dhimant Harkisan Desai
• 金额: $ 7.72万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-09 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590100
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aberrant crypt foci; Animal Model; Animals; Apoptosis; Behavior Therapy; Biodistribution; Biological Assay; Cancer Control; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Cleaved cell; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Diet; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Event; Exposure to; Future; Goals; Health; Human; In Vitro; Inbred F344 Rats; Injectable; Investigation; Laboratories; Laboratory Animal Models; Lead; Lesion; Literature; Malignant - descriptor; Malignant Neoplasms; Maximum Tolerated Dose; Micronutrients; Modeling; Nature; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phosphatidylinositide 3-Kinase Inhibitor; Prevention; Preventive; Proteins; Rattus; Reporting; Research; Rodent Model; Selenium; Signal Pathway; Signal Transduction; Specificity; Staging; Sulfur; Testing; Time; Tissues; Toxic effect; United States; Western Blotting; Western World; analog; base; cancer cell; cancer chemoprevention; cancer prevention; cancer therapy; chemotherapy; clinical efficacy; colon cancer cell line; design; effective intervention; efficacy testing; esophageal cancer prevention; human NOS2A protein; in vivo; inhibitor/antagonist; innovation; insight; intravenous injection; male; novel; pre-clinical; preclinical efficacy; premature; prevent; therapy development

DESCRIPTION (provided by applicant): The Overall objective of the project is to develop mechanism based iNOS / PI3 kinase inhibitor in addition to selenium to increase potency against colon cancer prevention. Several iNOS inhibitors have been reported for prevention of cancers. One such agents, S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isothiourea (PBIT) was effective inhibitor in vivo for colonic Aberrant crypt foci (ACF) and for prevention of esophageal cancer. Colorectal cancer (CRC) is one of the most common human malignancies in the western world, including United States. Preventive therapies are promising approach for treatment of cancer, and it has a potential to be a major component of colorectal cancer control. Due to the fact that conversion of normal colonic cells to malignant cells requires several steps and often proceeds over considerable time period, therefore there is an ample opportunity for the development of mechanism based preventive agents that may act at different stages of cancer. Recent studies have shown the importance of PI3 kinase signaling (Akt expression) and iNOS over-expressed in human colon tumors as well as in rodent models provides the basis to develop selective inhibitor of two major signaling pathways. The novel agent developed is called S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isoselenourea (PBISe), an isosteric selenium analog of PBIT. Preliminary results from our laboratory indicate that PBISe is >25 fold more potent than PBIT in four colon cancer cell lines tested in MTS assay. Western blot analysis showed decreased pAkt and Akt2 levels, and downstream pPRAS40 levels accompanied by an increase in cleaved PARP, an apoptosis markers demonstrating decreased PI3 kinase activity upon exposure to PBISe but not PBIT. Based on hypothesis and supportive preliminary data, we want to further develop PBISe for preclinical efficacy and pharmacological studies prior to the possible use in human clinical trials. We specifically propose to investigate the pharmacokinetics, pharmacodynamics, tissue distribution, and in vivo maximum tolerated dose (MTD) of PBISe administered by intravenous injection or diet in male F344 rat model.

描述（由申请人提供）： 该项目的总体目标是开发除硒之外的基于机制的 iNOS / PI3 激酶抑制剂，以提高预防结肠癌的效力。据报道，几种 iNOS 抑制剂可用于预防癌症。其中一种药物 S,S'-1,4-亚苯基-双(1,2-乙二基)双异硫脲 (PBIT) 是结肠异常隐窝病灶 (ACF) 的有效体内抑制剂，并可预防食道癌。结直肠癌（CRC）是包括美国在内的西方世界最常见的人类恶性肿瘤之一。预防性疗法是治疗癌症的一种有前景的方法，并且有可能成为结直肠癌控制的主要组成部分。由于正常结肠细胞向恶性细胞的转化需要几个步骤并且通常需要相当长的时间，因此有充分的机会开发可在癌症的不同阶段发挥作用的基于机制的预防剂。最近的研究表明，PI3 激酶信号传导（Akt 表达）和 iNOS 在人类结肠肿瘤以及啮齿动物模型中过表达的重要性为开发两种主要信号传导途径的选择性抑制剂提供了基础。开发的新型试剂称为 S,S'-1,4-亚苯基-双(1,2-乙二基)双-异硒脲 (PBISe)，是 PBIT 的等排硒类似物。我们实验室的初步结果表明，在 MTS 测定中测试的四种结肠癌细胞系中，PBISe 的效力比 PBIT 强 25 倍以上。蛋白质印迹分析显示 pAkt 和 Akt2 水平下降，下游 pPRAS40 水平下降，同时裂解的 PARP 增加，这是一种细胞凋亡标记物，表明暴露于 PBISe 后 PI3 激酶活性下降，但暴露于 PBIT 时则不然。基于假设和支持性初步数据，我们希望在可能用于人体临床试验之前进一步开发 PBISe 用于临床前功效和药理学研究。我们特别建议在雄性 F344 大鼠模型中研究通过静脉注射或饮食给予 PBISe 的药代动力学、药效学、组织分布和体内最大耐受剂量 (MTD)。