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

项目概述：头颈部鳞状细胞癌（HNSCC）被认为是由环境致癌物的影响引起的，包括烟草、酒精、槟榔液、有机溶剂、煤尘、焊接烟雾、石棉和多环芳烃。与HNSCC相关的发病率和死亡率主要源于其侵袭性和第二原发肿瘤（SPTs）的高发病率，这被认为是由原发肿瘤周围组织学正常组织的分子变化引起的。化学预防是一个重要的目标，旨在抵消致癌物质的影响和/或预防HNSCC的spt和复发。我们假设谷固酮，一种植物衍生的化合物，可能作为一种有效的预防治疗HNSCC。Guggulsterone以其降胆固醇活性而闻名，在临床配方中可作为膳食补充剂使用。它已被证明对前列腺癌、急性髓性白血病、肺癌和乳腺癌细胞具有抗癌活性，此外，还能抑制核因子KB （NFKB）的活性，NFKB是一种促进HNSCC和其他癌症肿瘤发生的转录因子。我们的初步研究表明，用谷胱甘酮治疗人HNSCC细胞可导致生长抑制、细胞凋亡、细胞周期阻滞和总酪氨酸和磷酸化酪氨酸（活化）信号传感器和转录激活因子(STAT)-3的减少，STAT -3是一种已知在大多数HNSCC肿瘤中具有组成性活性的致癌转录因子。本研究将通过体外研究细胞周期促进和抗凋亡基因（也是STATS和NFKB的靶点）水平的变化，探索谷固酮抗癌活性的分子机制。我们还将探讨guguulsterone诱导STATS水平下降的机制。最后，我们将通过使用两种HNSCC小鼠模型，异种移植模型和诱导TGF(3受体II缺失/K-Ras突变体，该突变体产生与人类相似的HNSCC肿瘤，在体内研究gugugulsterone的化学预防作用。本研究的目的是确定谷谷酮是否可用于HNSCC的化学预防，并阐明谷谷酮抗癌活性背后的分子机制，从而为其未来在临床试验中的应用提供坚实的基础。相关性：恶性鳞癌是一种极具破坏性的疾病，是全球第六大常见癌症。由于HNSCC是一种由环境暴露引起的疾病，而且与HNSCC相关的高水平发病率和死亡率是由第二原发肿瘤和复发引起的，因此预防HNSCC的方法有可能对公众健康产生重大影响。

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.