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: 7940968
• 负责人: ARUN K SHARMA
• 金额: $ 7.63万
• 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/7940968
• 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一个主要健康问题，约占总病例的 90%。尽管已经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，需要更有效的药物来安全地实现预防而不产生严重的副作用。新型化合物是天然产物的合理修饰，遵循相似的作用机制，但具有增强的效力、降低的毒性和较低的剂量需求，可能在临床上更有意义。最近，我们对天然和合成的异硫氰酸酯以及相应的新开发的硒类似物异硒氰酸酯进行了广泛的结构活性研究，确定异硒氰酸苯丁酯（ISC-4；Ph-(CH2)4-N=C=Se）是最有效的抗癌剂。研究发现，ISC-4 在抑制各种癌细胞的细胞生长方面比所有其他研究的硫和硒类似物（包括相应的异硫氰酸苯丁酯（PBITC；[Ph-(CH2)4-N=C=S]））更有效。诱导细胞凋亡和细胞周期停滞，并抑制细胞增殖。它有效抑制 PI3K/Akt 信号通路，减少黑色素瘤生长，约 60%，且没有任何全身毒性，在 0.76 5M 剂量下，PBITC 没有显示出任何肿瘤大小的减小。我们的假设是，ISC-4 保留了 ITC 作用的机制（抑制 I 期酶并诱导 II 期酶；阻断细胞周期进程并诱导细胞凋亡），并包括硒的附加化学预防作用，从而成为一种有效而安全的肺癌药物预防。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 CYP450 酶活性，诱导 II 相酶的表达和活性，并显着减少 A/J 小鼠中吡哆醇丁基 (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）诱导的致癌作用的作用，并了解这种活性是否是 ISC-4 或其活性代谢物之一所致。该提案的目的是验证 ISC-4 抑制 NNK 诱导的肺癌发展的功效。检验我们的假设并实现本申请目标的具体目的是 (1) 确定 ISC-4 在 A/J 小鼠肺癌模型中的化学预防功效，以及 (2) 确定口服给药的效率ISC-4 或其代谢物到达 A/J 小鼠的靶器官（肺）。我们将使用实验方法评估饮食ISC-4抑制口服NNK的A​​/J小鼠肿瘤发展的有效性，并使用[14C] ISC-4在A/J小鼠中进行生物分布研究以确定ISC是否有效-4或其代谢物到达肺部。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作为一种有效且安全的化学预防剂的验证将减少吸烟者/前吸烟者患肺癌的机会，从而直接降低死亡率。

项目成果

Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway.

• DOI: 10.1016/j.bmc.2011.08.044
• 发表时间: 2011-10-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Krishnegowda, Gowdahalli;Gowda, A. S. Prakasha;Tagaram, Hephzibah Rani S.;Carroll, Kevin F. Staveley-O';Irby, Rosalyn B.;Sharma, Arun K.;Amin, Shantu
• 通讯作者: Amin, Shantu

The Akt inhibitor ISC-4 synergizes with cetuximab in 5-FU-resistant colon cancer.

• DOI: 10.1371/journal.pone.0059380
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Allen JE;Gallant JN;Dicker DT;Amin S;Irby RB;Sharma AK;El-Deiry WS
• 通讯作者: El-Deiry WS

In vitro growth inhibition of human cancer cells by novel honokiol analogs.

• DOI: 10.1016/j.bmc.2012.03.062
• 发表时间: 2012-05-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Lin, Jyh Ming;Gowda, A. S. Prakasha;Sharma, Arun K.;Amin, Shantu
• 通讯作者: Amin, Shantu

The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.

• DOI: 10.1158/1078-0432.ccr-10-2370
• 发表时间: 2011-07-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Sharma AK;Kline CL;Berg A;Amin S;Irby RB
• 通讯作者: Irby RB