ISC-4 as a Novel Lung Cancer Chemopreventive Agent

ISC-4 作为新型肺癌化学预防剂

• 批准号: 7792948
• 负责人: ARUN K SHARMA
• 金额: $ 7.64万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792948
• 关键词: A/J Mouse; ADME Study; Accounting; Adverse effects; Antineoplastic Agents; Apoptosis; Beta Carotene; Biodistribution; Biological Factors; Biological Models; Butanones; Cancer Model; Carcinogenesis Inhibition; Carcinogens; Cell Cycle Arrest; Cell Cycle Progression; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; DNA Adducts; Development; Dose; Effectiveness; Enzymes; Evaluation; Exhibits; Goals; Health; Human; Incidence; Investigation; Isothiocyanates; Isotretinoin; Laboratories; Lead; Liver; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolism; Modification; Organ; Pharmaceutical Preparations; Phase; Prevention; Prevention strategy; Preventive; Preventive Intervention; Research; Safety; Selenium; Series; Signal Pathway; Smoker; Smoking Prevention; Staging; Structure; Sulfur; Testing; Time; Tobacco use; Tobacco-Associated Carcinogen; Tocopherols; Toxic effect; United States; Validation; Work; analog; base; cancer cell; carcinogenesis; cell growth; design; efficacy testing; enzyme activity; feeding; high risk; in vivo; insight; lung cancer prevention; melanoma; metabolic abnormality assessment; mortality; novel; preclinical study; prevent; radioactivity analysis; research study; smoking cessation; tool; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): Lung cancer remains a major health problem for smokers who account for ~90% of the total cases. Despite the identification of several preventive agents and strategies, optimal prevention of lung cancer has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds which are rational modifications of natural products and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. Recently, our extensive structure-activity study involving naturally occurring and synthetic isothiocyanates and corresponding newly developed selenium analogs, the isoselenocyanates, have identified phenylbutyl isoselenocyanate (ISC-4; Ph-(CH2)4-N=C=Se) as the most efficacious anti-cancer agent. ISC-4 was found to be more effective than all other sulfur and selenium analogs studied, including corresponding phenylbutyl isothiocyanate (PBITC; [Ph-(CH2)4-N=C=S]), in inhibiting cell growth in various cancer cells, inducing apoptosis and cell cycle arrest, and inhibiting cell proliferation. It effectively inhibited PI3K/Akt signaling pathway and reduced melanoma tumor growth, by about 60%, without any systemic toxicity, at 0.76 5M dose at which PBITC did not show any reduction in tumor size. Our hypothesis is that ISC-4 retains mechanistic aspects of ITCs action (inhibit Phase I and induce Phase II enzymes; block cell-cycle progression and induce apoptosis) and include added chemopreventive effects of selenium, resulting in a potent yet safe drug for lung cancer prevention. Our preliminary studies supported our hypothesis and have shown ISC-4 to be a promising lung cancer chemopreventive agent. It significantly inhibited CYP450 enzyme activity, induced expression and activity of Phase II enzymes, and substantially reduced formation of pyridoxobutyl (pob)-DNA adducts in A/J mice. The goal of this study is to evaluate this rationally designed agent against NNK (a tobacco carcinogen) induced carcinogenesis and to understand if this activity is due to ISC-4 or one of its active metabolites. The objective of this proposal is to validate the efficacy of ISC-4 for inhibiting NNK induced lung cancer development. The specific aims to test our hypothesis and to accomplish the objectives of this application are (1) To determine the chemopreventive efficacy of ISC-4 in the A/J mouse lung cancer model, and (2) To determine the efficiency at which orally administered ISC-4 or its metabolites reach the target organ (lung) in A/J mice. We will use the experimental approach of evaluating effectiveness of dietary ISC-4 for inhibiting tumor development in A/J mice fed orally with NNK, and carry out the biodistribution study in A/J mice using [14C] ISC-4 to determine if ISC-4 or its metabolites reach the lung. These studies will begin establishing the potential of ISC-4 as lung cancer preventive agent. Long term, validation of ISC-4 as an effective and safe chemopreventive agent would reduce the chances of developing lung cancer in smokers/former smokers thereby directly decreasing the mortality incidence.

描述（由申请人提供）： 肺癌仍然是吸烟者的主要健康问题，占总病例的约90%。尽管确定了几种预防药物和策略，但尚未实现肺癌的最佳预防。因此，需要更有效的药物，可以安全地实现预防，而不会产生严重的副作用。作为天然产物的合理修饰并遵循类似作用机制的新型化合物，但具有增强的效力、降低的毒性和较低的剂量要求，可能在临床上更相关。最近，我们广泛的结构-活性研究涉及天然存在的和合成的异硫氰酸酯和相应的新开发的硒类似物，异硒代氰酸酯，已确定异硒代氰酸苯丁酯（ISC-4; Ph-（CH 2）4-N=C=Se）作为最有效的抗癌剂。发现ISC-4在抑制各种癌细胞中的细胞生长、诱导细胞凋亡和细胞周期停滞以及抑制细胞增殖方面比所研究的所有其它硫和硒类似物（包括相应的异硫氰酸苯丁酯（PBITC; [Ph-（CH 2）4-N=C=S]））更有效。在0.76 μ M剂量下，它有效地抑制PI 3 K/Akt信号通路并使黑色素瘤肿瘤生长减少约60%，而没有任何全身毒性，在该剂量下，PBITC没有显示出肿瘤大小的任何减小。我们的假设是，ISC-4保留了ITC作用的机制方面（抑制I相酶并诱导II相酶;阻断细胞周期进程并诱导凋亡），并包括硒的额外化学预防作用，从而成为一种有效而安全的肺癌预防药物。我们的初步研究支持我们的假设，并已显示ISC-4是一个有前途的肺癌化学预防剂。在A/J小鼠中，它显著抑制CYP 450酶活性，诱导II相酶的表达和活性，并显著减少吡哆丁酯（pob）-DNA加合物的形成。本研究的目的是评估这种合理设计的药物对NNK（一种烟草致癌物）诱导的致癌作用，并了解这种活性是否是由于ISC-4或其活性代谢产物之一。本提案的目的是验证ISC-4抑制NNK诱导的肺癌发展的功效。测试我们的假设和实现本申请的目的的具体目的是（1）确定ISC-4在A/J小鼠肺癌模型中的化学预防功效，和（2）确定口服施用的ISC-4或其代谢物到达A/J小鼠中的靶器官（肺）的效率。我们将使用评价饮食ISC-4抑制口服NNK的A/J小鼠中肿瘤发展的有效性的实验方法，并使用[14 C] ISC-4在A/J小鼠中进行生物分布研究以确定ISC-4或其代谢物是否到达肺。这些研究将开始确定ISC-4作为肺癌预防剂的潜力。从长远来看，ISC-4作为一种有效和安全的化学预防剂的验证将降低吸烟者/前吸烟者患肺癌的机会，从而直接降低死亡率。