Phenolic antioxidants as tumor radio/chemosensitizers

描述(申请人提供)：与3，4-二羟基肉桂酸相关的植物酚类抗氧化剂显示出强大的抗肿瘤活性，包括抗增殖、抗有丝分裂和抗血管生成特性。该家族的两个结构相关的成员，咖啡酸苯乙酯(CAPE)和姜黄素，已被证明在体外优先诱导转化细胞而不是未转化细胞的凋亡，并在实验小鼠肿瘤模型中抑制息肉形成，几乎没有明显的毒性。CAPE和姜黄素的抗肿瘤活性归因于它们的抗氧化性能和抑制核因子Kappa-B/COX-2途径的能力。在初步研究中，PI表明CAPE和姜黄素抑制原癌基因激酶Akt/PKB的激活，而Akt/PKB位于NF-kB激活的上游。AKT在多种肿瘤中异常激活，促进细胞存活、细胞增殖和血管生成。PI还表明，CAPE对结直肠癌细胞具有很强的放射和化学增敏特性。由于Akt通路与抗电离辐射和增加血管生成有关，PI认为CAPE和姜黄素将是治疗实体瘤的有用的放射增敏、化学增敏和抗血管生成药物。在目标1中，对结直肠癌细胞的初步研究将扩展到脑和前列腺细胞系以及肿瘤异种移植。目标2将阐述Akt信号通路或其他抗凋亡通路是否是CAPE和姜黄素放射增敏的主要靶点。在目标3中，CAPE和姜黄素优先诱导转化细胞氧化应激增加的作用将被评估为潜在的放射增敏机制。目的将ALMS 1-3中的研究扩展到肿瘤放射增敏和正常组织损伤的动物模型，以检测CAPE和姜黄素在体内诱导肿瘤放射增敏和保护正常组织免受辐射损伤的能力。这些研究的结果将为这类天然化合物显示的放射/化学增敏特性奠定分子基础，并将为使用CAPE和/或姜黄素作为化疗药物和辐射剂量调节剂的临床试验的设计奠定基础。

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.