Lung Cancer Chemoprevention using Deguelin

使用 Deguelin 进行肺癌化学预防

• 批准号: 7465577
• 负责人: HO-YOUNG LEE
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465577
• 关键词: A/J Mouse; Address; Adenovirus Vector; Adenoviruses; Angiogenesis Inhibition; Animal Model; Apoptosis; Apoptotic; Benzo(a)pyrene; Bilateral; Binding; Biochemical; CDK4 gene; Cancer cell line; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; Chromosomes; Client; Count; Development; Diagnosis; Disease; Disease Progression; Dominant-Negative Mutation; Dose; Drug Kinetics; Dysplasia; EGFR Protein Overexpression; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Event; Fabaceae; Family; Figs - dietary; Genetic; Goals; Growth; Growth Factor Receptors; Half-Life; Heat-Shock Proteins 90; Homologous Gene; Human; Hyperplasia; Immunologic Surveillance; In Vitro; Incidence; Induction of Apoptosis; Infection; Insulin-Like Growth Factor Receptor; Intervention; LY294002; Lead; Lesion; Ligands; Longevity; Lung Neoplasms; MEKs; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metaplasia; Modeling; Molecular; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Oral; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Play; Premalignant; Principal Investigator; Property; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Rate; Rattus; Receptor Protein-Tyrosine Kinases; Regulation; Retroviridae; Role; Secondary to; Signal Pathway; Smoker; Specimen; Squamous Metaplasia; Staging; Structure; Structure of parenchyma of lung; System; TP53 gene; Tamoxifen; Telomerase; Testing; Therapeutic; Time; Tissues; Tobacco; Toxic effect; Transforming Growth Factor alpha; Transforming Growth Factors; Transgenic Mice; Treatment Efficacy; Ubiquitination; United States; Viral; Xenobiotic Metabolism; adenoma; angiogenesis; base; cancer cell; cell transformation; chemotherapeutic agent; cyclooxygenase 2; cytotoxicity; deguelin; dosage; in vivo; lung carcinogenesis; lung tumorigenesis; mortality; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel strategies; oncogene protein v-akt; prevent; programs; protein degradation; protein expression; size; tensin; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): In the United States, lung cancer leads all other cancers in both incidence and mortality rate. Clearly, there is an urgent need to develop novel chemopreventive and therapeutic approaches for lung cancer. Toward this goal, we have investigated novel strategies targeting intracellular mechanisms that promote survival and suppress apoptosis of premalignant and malignant human bronchial epithelial (HBE) cells and lung cancer cells. One effective strategy is to use the deguelin, isolated from Mundulea sericea (Leguminosae), which targets Akt that plays a major role in cell survival, transformation, end apoptosis. This proposal is based on findings which have shown that: A) Akt is constitutively active in pramalignant and malignant HBE cells. B) Akt is also highly active in most NSCLC cell lines, probably owing to the activating mutations of ras, overexpression of the tyrosine kinase receptor EGFR family and one of its ligands, transforming growth factor alpha (TGF-alpha), elevated levels of the subunits of PI3K, and reduced level of PTEN expression. C) Activation of Akt is an early biochemical effect of tobacco components; increased expression of pAkt (Ser473) has been observed in reactive epithelium specimens (bronchial hyperplasia and squamous metaplasia), bronchial dysplasia, and NSCLC from current and formal smokers. D) Targeting the Akt pathway using pharmacological or genetic approaches efficiently inhibited Akt activity and suppressed the proliferation of premalignant and malignant HBE cells as well as NSCLC cells without detectable cytotoxicity on normal HBE cells. E) Deguelin strongly inhibited Akt activity, in association with suppression of the growth and induction of apoptosis in premalignant and malignant HBE cells as well as a subset of NSCLC cells, with minimum effects on normal HBE cells at in vitro dosages attainable in vivo. F) Deguelin also inhibited expression of COX-2, which is largely regulated by Akt, that participates in xenobiotic metabolism, angiogenesis, inhibition of immune surveillance, and suppression of apoptosis during tumorigenesis. G) Pharmacokinetic studies in rats and mouse showed that a nontoxic dose of deguelin (1 mu/M), delivered intravenously or by oral gavage, is achievable in a variety of tissues in vivo, including lung tissue. All of these findings provide a strong rationale to use deguelin as a chemopreventive and/or chemotherapeutic agent in lung cancer. We recently found that deguelin decreased the levels of a subset of client proteins of heat-shock protein 90, including PDK-1 and Akt, in NSCLC cells, suggesting that deguelin inactivated APt pmt|y by regulating the function of Hsp90. These and other studies have led to the following hypotheses: 1) Akt activation is sufficient for HBE cell transformation and is required for the survival of transformed HBE cells. 2) Inhibition of Akt activity prevents lung tumor development. 3) Deguelin inactivates Akt by decreasing stability of PDK-1 and Akt through blockade of Hsp90 in transformed HBE and NSCLC cells. In this RO1 application, I propose to test these hypotheses by exploring the following Specific Aims: 1) To determine whether constitutive activation of the Akt induces malignant transformation of HBE cells. 2) To determine whether inhibition of Akt activity by deguelin demonstrates lung cancer chemopreventive and/or therapeutic activity in mouse models of lung cancer. 3) To investigate the mechanism through which deguelin inactivates Akt in transformed HBE cells and NSCLC cells. We expect that evaluating the chemopreventive/chemotherapeutic activities of deguelin in animal model of lung cancer and understanding the mechanism by which deguelin regulates Akt activity may lead to the development of novel strategies for chemoprevention as well as treatment in lung cancer.

描述(申请人提供)：在美国，肺癌的发病率和死亡率均居所有其他癌症之首。显然，迫切需要开发新的肺癌化学预防和治疗方法。为了实现这一目标，我们研究了针对细胞内机制的新策略，这些机制可以促进癌前和癌变的人支气管上皮细胞(HBE)和肺癌细胞的存活和抑制凋亡。一种有效的策略是使用从丝光绿藻(豆科)中分离出来的鱼藤素，它针对在细胞生存、转化和最终凋亡中发挥主要作用的Akt。这一建议是基于以下发现：a)Akt在癌前和恶性HBE细胞中具有结构性活性。B)Akt在大多数NSCLC细胞系中也高度活跃，可能是由于ras的激活突变，酪氨酸激酶受体EGFR家族及其配体的过度表达，转化生长因子α(TGF-α)，PI3K亚单位的水平升高，以及PTEN表达的降低。C)Akt的激活是烟草成分的早期生化效应；在反应性上皮标本(支气管增生和鳞状化生)、支气管不典型增生以及当前和正式吸烟者的NSCLC中观察到Akt(Ser473)的表达增加。D)通过药理学或遗传学方法靶向Akt途径，有效地抑制Akt活性，抑制癌前和恶性HBE细胞以及非小细胞肺癌细胞的增殖，而对正常HBE细胞没有明显的细胞毒性。E)Dguelin强烈抑制Akt活性，与抑制癌前和恶性HBE细胞以及部分NSCLC细胞的生长和诱导凋亡有关，在体内可获得的体外剂量下，对正常HBE细胞的影响最小。F)Dguelin还抑制了环氧合酶-2的表达，环氧合酶-2在很大程度上受Akt的调节，参与了异种代谢、血管生成、抑制免疫监视和抑制肿瘤发生过程中的细胞凋亡。G)大鼠和小鼠的药代动力学研究表明，静脉或口服无毒剂量的鱼藤素(1 mU/M)可在体内的各种组织中实现，包括肺组织。所有这些发现为使用鱼藤素作为肺癌的化学预防和/或化疗药物提供了强有力的理由。我们最近发现，鱼腥草素降低了NSCLC细胞中热休克蛋白90客户蛋白的一部分的水平，包括PDK-1和Akt，这表明鱼腥草素通过调节Hsp90的功能来灭活apt PMT|y。这些研究和其他研究得出了以下假设：1)Akt的激活对于HBE细胞的转化是足够的，并且是转化的HBE细胞生存所必需的。2)抑制Akt活性可阻止肺癌的发生。3)鱼藤素通过阻断转化的HBE和NSCLC细胞中的Hsp90，降低PDK-1和Akt的稳定性，从而使Akt失活。在RO1的应用中，我建议通过探索以下特定目标来检验这些假设：1)确定Akt的结构性激活是否会诱导HBE细胞恶性转化。2)确定鱼藤素抑制Akt活性是否具有肺癌的化学预防和/或治疗作用。3)探讨鱼藤素对转化的HBE细胞和NSCLC细胞Akt失活的机制。我们期望在肺癌动物模型中评价鱼藤素的化学预防/化疗活性，并了解鱼藤素调节Akt活性的机制，可能会导致肺癌化学预防和治疗的新策略的发展。