Targeting multiple skin cancer pathways using citrus auraptene and ATRA

使用金柑橘和 ATRA 靶向多种皮肤癌途径

• 批准号: 8046863
• 负责人: HEATHER E KLEINER
• 金额: $ 18.79万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046863
• 关键词: Address; American; Anchorage-Independent Growth; Apoptosis; Biological; Caucasians; Caucasoid Race; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemopreventive Agent; Citrus; Citrus Fruit; Clone Cells; Development; Disease; Dominant-Negative Mutation; Dose; Effectiveness; Epithelial; Genes; Genetic Suppression; Goals; Growth; HIV; Health; Human; Immunocompromised Host; Individual; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Mus; Not Hispanic or Latino; Organ Transplantation; Pathway interactions; Patients; Play; Population; Prevention strategy; Preventive; Property; Regulation; Research; Risk; Role; SCID Mice; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Solid; Squamous cell carcinoma; Staging; Stat3 Signaling Pathway; Testing; Therapeutic; Toxic effect; Transplant Recipients; Tretinoin; Tumor Volume; Tumor-Derived; Tumorigenicity; Vitamin A; Xenograft Model; angiogenesis; base; cancer cell; cancer type; cell motility; cell type; chemical carcinogenesis; genetic inhibitor; high risk; immunodeficient mouse model; improved; in vitro Assay; in vivo; inhibitor/antagonist; malignant phenotype; novel; older patient; prevent; research study; skin squamous cell carcinoma; small hairpin RNA; transcription factor; treatment effect; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): There is an increasing need for safe, long-term preventive treatments for non-melanoma skin cancer (NMSC), which is a particular threat to high risk groups such as the growing populations of immunocompromised solid organ transplant patients, HIV patients, and elderly non-Hispanic Caucasians. We have shown that a combination of the well-characterized chemopreventive vitamin A metabolite, all-trans retinoic acid (ATRA), with the bioactive dietary agent auraptene (AUR), can synergistically or supra-additively suppress skin squamous cell carcinoma (SCC) tumor growth in a mouse xenograft model. A long-term goal of our research is to develop effective chemopreventive treatments for epithelial cancers. In keeping with this goal, the primary aim of this project is to gain a better understanding of the effects of ATRA, and AUR on the development of skin SCC. Our overall hypothesis is that the ATRA + AUR combination is more effective than either agent alone due to the ability of ATRA to suppress Stat3 signaling, and AUR to suppress the NF-:B pathway and other pathways. Stat3 is a transcription factor that controls cell proliferation and survival, and is important in the regulation of apoptosis, proliferation, motility, and angiogenesis, all hallmarks of malignancy. Our laboratories and others have shown that Stat3 activity is constitutive in several malignant cell types and is required for initiation, promotion and progression to a more malignant phenotype in skin SCC. NF-:B is a survival signaling transcription factor also involved in the malignant phenotype of many cancers, including SCCs. Our preliminary results show that the ATRA+AUR combination suppresses the growth of tumors derived from the human skin SCC cell line SRB12-p9 (P9 WT), in the severe combined immunodeficient (SCID) mouse orthotopic tumorigenesis model. We will first examine the effects of a wider range of doses of ATRA 1 AUR against tumor volume in SCID mice. We will compare the effects of AUR treatment in the context of pharmacological suppression of Stat3 (ATRA treatment) to genetic suppression of Stat3, (stable expression of a dominant negative acting form of Stat3; S3DN cells). Tumors will be analyzed in detail for malignant properties and for suppression of Stat3 and NF-:B pathways. We will further verify our hypothesis by genetically blocking the Stat3 pathway (S3DN cells) and the NF-:B pathway (shRNA mediated knockdown of NF-:B), alone and in combination, in the P9WT SCC cells. The tumorigenic properties of the resulting pathway suppressed cells will be determined. PUBLIC HEALTH RELEVANCE: The goal of this project is to provide evidence that the combination of all-trans retinoic acid, a vitamin A derivative, with a citrus derived compound, auraptene, will provide an enhanced effect to prevent non- melanoma skin cancer development. The relevance of this project to human health is that non-melanoma skin cancer afflicts more than one million Americans every year, and can result in debilitating disease and even death. Furthermore, certain populations, such as solid organ transplant patients (> 173,000 as of 2006), HIV patients, and other immunocompromised individuals are at a greatly increased risk for these types of cancers. Novel prevention strategies that increase effectiveness while limiting toxicity would therefore be desirable.

描述（由申请人提供）：对非黑色素瘤皮肤癌 (NMSC) 的安全、长期预防性治疗的需求日益增长，这对高危人群尤其构成威胁，例如不断增长的免疫功能低下的实体器官移植患者、艾滋病毒患者和老年非西班牙裔白种人。我们已经证明，在小鼠异种移植模型中，充分表征的化学预防性维生素 A 代谢物全反式视黄酸 (ATRA) 与生物活性膳食剂 auraptene (AUR) 的组合可以协同或超累加地抑制皮肤鳞状细胞癌 (SCC) 肿瘤的生长。我们研究的长期目标是开发针对上皮癌的有效化学预防疗法。为了实现这一目标，该项目的主要目的是更好地了解 ATRA 和 AUR 对皮肤鳞状细胞癌发展的影响。我们的总体假设是，ATRA + AUR 组合比单独使用任一药物更有效，因为 ATRA 能够抑制 Stat3 信号传导，而 AUR 能够抑制 NF-:B 通路和其他通路。 Stat3 是一种控制细胞增殖和存活的转录因子，在细胞凋亡、增殖、运动和血管生成（所有恶性肿瘤的标志）的调节中发挥着重要作用。我们的实验室和其他实验室已经表明，Stat3 活性是多种恶性细胞类型的组成型，并且是皮肤鳞状细胞癌中起始、促进和进展为更恶性表型所必需的。 NF-:B 是一种生存信号转录因子，也参与许多癌症（包括鳞状细胞癌）的恶性表型。我们的初步结果表明，在严重联合免疫缺陷 (SCID) 小鼠原位肿瘤发生模型中，ATRA+AUR 组合可抑制源自人皮肤 SCC 细胞系 SRB12-p9 (P9 WT) 的肿瘤的生长。我们将首先检查更大范围的 ATRA 1 AUR 剂量对 SCID 小鼠肿瘤体积的影响。我们将比较 AUR 治疗在 Stat3 药理学抑制（ATRA 治疗）和 Stat3 基因抑制（Stat3 显性失活形式的稳定表达；S3DN 细胞）背景下的效果。将详细分析肿瘤的恶性特性以及 Stat3 和 NF-:B 通路的抑制。我们将通过在 P9WT SCC 细胞中单独或组合地从基因上阻断 Stat3 通路（S3DN 细胞）和 NF-:B 通路（shRNA 介导的 NF-:B 敲低）来进一步验证我们的假设。将确定所得途径抑制细胞的致瘤特性。 公共健康相关性：该项目的目标是提供证据，证明全反式视黄酸（一种维生素 A 衍生物）与柑橘衍生化合物 auraaptene 的组合将增强预防非黑色素瘤皮肤癌发展的效果。该项目与人类健康的相关性在于，非黑色素瘤皮肤癌每年困扰超过一百万美国人，并可能导致衰弱性疾病甚至死亡。此外，某些人群，例如实体器官移植患者（截至 2006 年超过 173,000 人）、艾滋病毒患者和其他免疫功能低下的个体，患这些类型癌症的风险大大增加。因此，需要一种既能提高有效性又能限制毒性的新型预防策略。