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）： 肺癌仍然是一个主要的健康问题，对于占总病例的90％的吸烟者来说。尽管确定了几种预防剂和策略，但尚未实现最佳预防肺癌。因此，需要更有效的药物，可以安全地实现预防，而无需剧烈的副作用。新颖的化合物是天然产物的合理修饰并遵循类似的作用机理，但是效力增强，毒性降低和剂量要求降低，可能在临床上更相关。最近，我们广泛的结构活性研究涉及自然发生和合成异硫氰酸酯以及相应的新开发的硒类似物，异苯苯甲氰酸酯，已经确定苯基丁基异氰酸酯（ISC-4; isc-4; pH-（CH2）4-N = C = SE）是最有效的抗抗癌药物。发现ISC-4比所研究的所有其他硫和硒类似物更有效，包括相应的苯基丁基异硫氰酸酯（PBITC； [PH-（CH2）4-N = C = S]），抑制各种癌细胞的细胞生长，诱导细胞凋亡和细胞周期停滞，并抑制细胞的细胞增殖。它有效地抑制了PI3K/AKT信号通路，并降低了黑色素瘤肿瘤生长，大约60％，没有任何全身毒性，pBITC的剂量为0.76 5m，在该剂量下没有显示任何肿瘤大小的降低。我们的假设是，ISC-4保留了ITC作用的机械方面（抑制I期并诱导II期酶；阻止细胞周期的进展并诱导凋亡），并包括硒的化学预防作用，从而导致预防肺癌的有效但安全的药物。我们的初步研究支持了我们的假设，并表明ISC-4是一种有前途的肺癌化学预防剂。它显着抑制了CYP450酶的活性，II期酶的诱导表达和活性，并大大降低了A/J小鼠中吡二昔布基（POB） - DNA加合物的形成。这项研究的目的是评估这种针对NNK（烟草致癌物）诱导的致癌作用的合理设计的药物，并了解该活性是否是由于ISC-4还是其活性代谢产物引起的。该提案的目的是验证ISC-4对抑制NNK诱导肺癌发展的功效。 （1）确定A/J小鼠肺癌模型中ISC-4的化学预防疗效，以及（2）确定在A/J鼠标中A/J鼠标中的代谢物到达目标器官（肺）。我们将使用实验方法评估饮食ISC-4的有效性，以抑制用NNK口语喂养的A/J小鼠的肿瘤发育，并使用[14C] 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。这些研究将开始确立ISC-4作为肺癌预防剂的潜力。从长远来看，将ISC-4作为一种有效且安全的化学预防剂的验证将减少吸烟者/前吸烟者中患肺癌的机会，从而直接降低死亡率的发生。