Phenolic antioxidants as tumor radio/chemosensitizers

酚类抗氧化剂作为肿瘤放射/化学增敏剂

• 批准号: 7049385
• 负责人: Constantinos Koumenis
• 金额: $ 24.91万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-02 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049385
• 关键词: antineoplastics; antioxidants; apoptosis; athymic mouse; brain neoplasms; catechols; cell line; chemosensitizing agent; colorectal neoplasms; free radicals; ionizing radiation; neoplasm /cancer transplantation; neoplastic cell; neoplastic transformation; nuclear factor kappa beta; oxidative stress; plant extracts; prostate neoplasms; radioprotective agents; radiosensitizer; serine threonine protein kinase; superoxide dismutase

DESCRIPTION (provided by applicant): Plant phenolic antioxidants related to the 3, 4-dihydroxycinammic acid exhibit potent antitumor activities, including anti-proliferative, anti-mitogenic and anti-angiogenic properties. Two structurally-related members of this family, Caffeic Acid Phenethyl Ester (CAPE) and curcumin, have been shown to preferentially induce apoptosis in transformed but not untransformed cells in vitro, and to inhibit polyp formation in experimental mouse tumor models with little or no overt toxicity. The anti-tumorigenic activity of CAPE and curcumin have been attributed to their antioxidant properties and their ability to inhibit the Nuclear Factor Kappa-B/COX-2 pathway. In preliminary studies, the PI has shown that CAPE and curcumin inhibit activation of the protooncogene kinase, Akt/PKB, that lies upstream of NF-kB activation. Akt is abnormally activated in a variety of tumors and promotes cell survival, cell proliferation and angiogenesis. The PI also has shown that CAPE exhibits potent radio- and chemosensitization properties against colorectal carcinoma cells. Since the Akt pathway is associated with resistance to ionizing radiation and increased angiogenesis, the PI proposes that CAPE and curcumin will be useful radiosensitizing, chemosensitizing, and anti-angiogenic agents for the treatment of solid tumors. In Aim 1, the preliminary studies in colorectal carcinoma cells will be extended to brain and prostate cell lines and tumor xenografts. Aim 2 will address whether the Akt signalling pathway or other anti-apoptotic pathways are the primary targets for CAPE and curcumin radiosensitization. In Aim 3, the role of increased oxidative stress induced preferentially in transformed cells by CAPE and curcumin will be evaluated as a potential radiosensitization mechanism. Aim 4 will extend the studies in Alms 1-3 to animal models of tumor radiosensitization and normal tissue injury to examine the ability of CAPE and curcumin to induce in vivo tumor radiosensitization and protect normal tissues fro radiation injury. Results from these studies will establish the molecular basis for the demonstrated radio/chemosensitizing properties of this class of naturally occurring compounds and will also set the stage for the design of clinical trials using CAPE and/or curcumin as chemotherapeutic agents and radiation dose modifiers.

描述（由申请人提供）：与3，4-二羟基霉素酸有关的植物酚类抗氧化剂表现出有效的抗肿瘤活性，包括抗增殖性，抗差异性和抗血管生成特性。该家族的两个与结构相关的成员，咖啡酸苯乙酯（CAPE）和姜黄素已被证明在体外会优先诱导转化但未转化的细胞中的凋亡，并抑制少量或没有明显毒性的实验小鼠肿瘤模型中的念珠菌形成。 CAPE和姜黄素的抗肿瘤活性归因于其抗氧化特性及其抑制核因子Kappa-B/Cox-2途径的能力。在初步研究中，PI表明，斗篷和姜黄素抑制了NF-KB激活上游的原子量激酶AKT/PKB的激活。 AKT在多种肿瘤中被异常激活，并促进细胞存活，细胞增殖和血管生成。 PI还表明，斗篷对结直肠癌细胞具有有效的放射性和化学敏化特性。由于AKT途径与对电离辐射的抗性和血管生成增加有关，因此PI提出，CAPE和姜黄素将是有用的放射激素，化学敏化和抗血管生成剂来治疗实体瘤。 在AIM 1中，大肠癌细胞的初步研究将扩展到大脑，前列腺细胞系和肿瘤异种移植物。 AIM 2将解决AKT信号通路还是其他抗凋亡途径是CAPE和姜黄素放射敏化的主要目标。 在AIM 3中，将通过CAPE和CURCUMIN在转化的细胞中优先诱导氧化应激的作用，以作为潜在的放射敏化机制评估。 AIM 4将将施舍1-3的研究扩展到肿瘤放射敏化和正常组织损伤的动物模型，以检查斗篷和姜黄素在体内肿瘤放射敏感性诱导并保护正常组织的能力。这些研究的结果将建立这类天然发生化合物的无线电/化学敏化特性的分子基础，并将为使用CAPE和/或姜黄素作为化学治疗剂和辐射剂量改性剂的临床试验设计阶段。