Prevention of Head and Neck Carcinogenesis with a Plant-Derived Compound

用植物源性化合物预防头颈癌

• 批准号: 7481024
• 负责人: Rebecca J Leeman-Neill
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481024
• 关键词: Acute Myelocytic Leukemia; Address; Adverse effects; Alcohols; Apoptosis; Apoptotic; Area; Aromatic Polycyclic Hydrocarbons; Asbestos; Breast Cancer Cell; Calpain; Carcinogens; Caspase; Cell Cycle; Cell Cycle Arrest; Cells; Chemoprevention; Chemopreventive Agent; Cholesterol; Clinical; Clinical Trials; Coal; Commiphora mukul; Complement; Daily; Development; Diagnosis; Disease; Down-Regulation; Drug Formulations; Dust; Electrophoretic Mobility Shift Assay; Environmental Carcinogens; Environmental Exposure; Enzymes; Exanthema Subitum; Exposure to; Future; Gene Targeting; Genes; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histologic; Human; Immunoblotting; In Vitro; Incidence; Inhibition of Apoptosis; Investigation; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; Medicine; Messenger RNA; Methods; Molecular; Molecular Carcinogenesis; Morbidity - disease rate; Mus; Neoplasms; Normal tissue morphology; Nuclear; Oncogenic; Organic solvent product; Patients; Phosphotyrosine; Plant Extracts; Plants; Polymerase Chain Reaction; Prevention; Preventive; Primary Neoplasm; Prostate; Proteins; Public Health; Rate; Recurrence; Regulation; Resources; Retinoids; STAT3 gene; Secondary Prevention; Serine Protease; Signal Pathway; Stat3 protein; Testing; Thinking; Time; Tobacco; Transgenic Organisms; Week; Welding; Work; Xenograft Model; anticancer activity; base; cancer therapy; carcinogenesis; dietary supplements; enzyme activity; expectation; in vivo; inhibitor/antagonist; leukemia; mortality; mouse model; multicatalytic endopeptidase complex; mutant; pregna-4,17-diene-3,16-dione; prevent; receptor; research study; small molecule; stem; transcription factor; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Project Summary: Head and neck squamous cell carcinoma (HNSCC) is thought to be caused by the effects of environmental carcinogens including tobacco, alcohol, betel quid, organic solvents, coal dust, welding fumes, asbestos, and polycyclic aromatic hydrocarbons. The morbidity and mortality associated with HNSCC largely stem from its invasiveness and the high incidence of second primary tumors (SPTs), which are thought to result from "field carcinogenesis," molecular changes in the histologically normal tissue surrounding the primary tumor. Chemoprevention, aimed at counteracting the effects of carcinogens and/or preventing HNSCC SPTs and recurrence, is an important goal. We hypothesize that guggulsterone, a plant- derived compound, may be efficacious as a preventive therapy for HNSCC. Guggulsterone, known for its cholesterol-lowering activity, is available in clinical formulations as a dietary supplement. It has been shown to having anticancer activity in prostate cancer, acute myeloid leukemia, lung cancer and breast cancer cells and, additionally, to suppress the activity of nuclear factor KB (NFKB), a transcription factor that promotes tumorigenesis in HNSCC and other cancers. Our preliminary studies show that treatment of human HNSCC cells with guggulsterone results in growth inhibition, apoptosis, cell cycle arrest and decreases in total and phosphotyrosine (activated) Signal Transducer and Activator of Transcription (STAT)-3, an oncogenic transcription factor known to be constitutively active in most HNSCC tumors. This study will explore the molecular mechanisms of guggulsterone's anticancer activity through in vitro investigation of changes in levels of cell-cycle-promoting and anti-apoptotic genes that are also targets for STATS and NFKB. The mechanism behind the guggulsterone-induced decrease in STATS levels will also be explored. Finally, guggulsterone's chemopreventive effects will be investigated in vivo through the use of two mouse models of HNSCC, a xenograft model and an inducible TGF(3 receptor II deletion/K-Ras mutant, which develops HNSCC tumors similar to those seen in humans. The goal of this work will be to ascertain whether or not guggulsterone may be used for Chemoprevention of HNSCC and to elucidate the molecular mechanism behind guggulsterone's anticancer activity, thus providing a firm basis for its future use in clinical trials. Relevance: HNSCC is an extraordinarily devastating disease and the sixth most common cancer worldwide. Because it is a disease caused by environmental exposures and because high levels of HNSCC- associated morbidity and mortality result from second primary tumors and recurrence, methods of preventing HNSCC have the potential to make a great impact on public health.

描述（由申请人提供）：项目摘要：头部和颈部鳞状细胞癌（HNSCC）被认为是由环境致癌物（包括烟草，酒精，槟榔，有机溶剂，有机溶剂，煤炭粉尘，焊接烟，石棉，石棉和多晶芳香芳香族氢碳植物）的影响引起的。与HNSCC相关的发病率和死亡率很大程度上源于其侵入性和第二个原发性肿瘤（SPT）的高发病率，这被认为是由“野外致癌作用”引起的，这是围绕原发性肿瘤的组织学正常组织的分子变化。旨在抵消致癌物和/或预防HNSCC SPT和复发的作用的化学预防是一个重要目标。我们假设Guggulsterone是一种植物衍生的化合物，可以有效作为HNSCC的预防疗法。 Guggulsterone以降低胆固醇的活性而闻名，可作为临床配方作为饮食补充剂提供。已显示出在前列腺癌，急性髓样白血病，肺癌和乳腺癌细胞中具有抗癌活性，并抑制核因子KB（NFKB）的活性，核因子KB（NFKB）是一种转录因子，促进了HNSCC和其他癌症的肿瘤发生。我们的初步研究表明，用guggulsterone对人类HNSCC细胞的治疗会导致生长抑制，凋亡，细胞周期停滞，总和磷酸酪氨酸（激活）信号转录器和转录激活剂（Stat）-3，已知的致癌转录因子（STAT）-3，已知在大多数HNSCC CCC CCCC tumors中具有强度活跃。这项研究将通过在体外研究细胞周期促进基因和抗凋亡基因的水平的变化，这些变化也是STAT和NFKB的靶标，探索Guggulsterone抗癌活性的分子机制。还将探索Guggulsterone诱导的Stats水平降低的机制。最后，将通过使用两个小鼠HNSCC模型，异种移植模型和一个可诱导的TGF（3受体II删除/K-RAS突变体）在体内研究Guggulsterone的化学预防作用，该模型会形成与人类相似的HNSCC肿瘤。阐明了古格酮的抗癌活性的分子机制，从而为临床试验提供了牢固的基础：HNSCC是一种非常毁灭性的疾病，是全球第六个最常见的癌症。对公共卫生产生重大影响。