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: 7657345
• 负责人: Rebecca J Leeman-Neill
• 金额: $ 4.19万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657345
• 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; 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; Prevention; Preventive; Primary Neoplasm; Prostate; Proteins; Public Health; Recurrence; Regulation; Resources; Retinoids; STAT3 gene; Secondary Prevention; Serine Protease; Signal Pathway; Stat3 protein; Testing; Time; Tobacco; Transgenic Organisms; 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; 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、煤尘、焊接烟雾、石棉和多环芳烃）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袭性和第二原发性肿瘤（SPT）的高发病率，第二原发性肿瘤被认为是由“现场致癌”引起的，即原发性肿瘤周围组织学正常组织中的分子变化。化学预防，旨在抵消致癌物的影响和/或预防HNSCC SPT和复发，是一个重要的目标。我们推测，guggulsterone，一种植物源性化合物，可能是有效的预防治疗HNSCC。Guggulsterone以其降胆固醇活性而闻名，可作为膳食补充剂用于临床制剂。已显示其在前列腺癌、急性髓性白血病、肺癌和乳腺癌细胞中具有抗癌活性，并且另外抑制核因子KB（NF KB）的活性，核因子KB是促进HNSCC和其他癌症中的肿瘤发生的转录因子。我们的初步研究表明，用guggulsterone处理人HNSCC细胞导致生长抑制、细胞凋亡、细胞周期停滞和总的和磷酸酪氨酸（活化的）信号转导和转录激活因子（STAT）-3（已知在大多数HNSCC肿瘤中具有组成性活性的致癌转录因子）的减少。本研究将通过体外研究细胞周期促进和抗凋亡基因水平的变化来探索guggulsterone抗癌活性的分子机制，这些基因也是STATS和NF κ B的靶点。还将探索guggulsterone诱导的STATS水平降低背后的机制。最后，通过使用两种HNSCC小鼠模型，异种移植模型和诱导型TGF β受体II缺失/K-Ras突变体，将在体内研究guggulsterone的化学预防作用，所述诱导型TGF β受体II缺失/K-Ras突变体产生类似于在人类中所见的HNSCC肿瘤。本工作的目的是确定guggulsterone是否可用于HNSCC的化学预防，并阐明guggulsterone抗癌活性背后的分子机制，从而为其未来的临床试验提供坚实的基础。相关性：HNSCC是一种极具破坏性的疾病，是全球第六大常见癌症。因为它是由环境暴露引起的疾病，并且因为高水平的HNSCC相关的发病率和死亡率由第二原发性肿瘤和复发引起，所以预防HNSCC的方法具有对公共健康产生巨大影响的潜力。