ISC-4 as a Novel Lung Cancer Chemopreventive Agent

描述(由申请人提供)： 肺癌仍然是吸烟者的主要健康问题，吸烟者约占总病例的90%。尽管已经确定了几种预防药物和策略，但尚未实现对肺癌的最佳预防。因此，需要更有效的制剂来安全地实现预防，而不会产生严重的副作用。新型化合物是对天然产物的合理修饰，遵循类似的作用机制，但具有增强效力、降低毒性和较低剂量要求的特点，可能在临床上更具相关性。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硫氰酸酯进行了广泛的构效研究，发现苯丁基异硫氰酸酯(ISC-4；Ph-(CH2)4-N=C=Se)是最有效的抗癌药物。研究发现ISC-4比所有其他硫和硒类似物，包括相应的苯丁基异硫氰酸酯(PBITC；[Ph-(CH2)4-N=C=S])更有效地抑制各种癌细胞的生长，诱导细胞凋亡和细胞周期停滞，并抑制细胞增殖。有效抑制PI3K/Akt信号通路，抑制黑色素瘤生长约60%，无全身毒性，0.76~5M剂量时，肿瘤体积无明显缩小。我们的假设是，ISC-4保留了ITCs作用的机械性方面(抑制I期和诱导II期酶；阻止细胞周期进展和诱导细胞凋亡)，并包括附加的硒的化学预防作用，从而产生一种有效而安全的肺癌预防药物。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药物。显著抑制细胞色素P450酶活性，诱导第二相酶的表达和活性，并显著减少吡哆丁基(POB)-DNA加合物的形成。本研究的目的是评价这种合理设计的抗NNK(一种烟草致癌物)诱导的致癌作用，并了解这种活性是否源于ISC-4或其活性代谢物之一。本提案的目的是验证ISC-4抑制NNK诱导的肺癌发展的有效性。检验我们的假设并实现这一应用的具体目的是(1)确定ISC-4在A/J小鼠肺癌模型中的化学预防效果，以及(2)确定口服ISC-4或其代谢产物到达A/J小鼠靶器官(肺)的效率。我们将采用评价饮食ISC-4对口服NNK的A/J小鼠肿瘤生长抑制效果的实验方法，并使用[14C]ISC-4在A/J小鼠体内进行生物分布研究，以确定ISC-4或其代谢产物是否到达肺。这些研究将开始确定ISC-4作为肺癌预防药物的潜力。从长远来看，确认ISC-4是一种有效和安全的化学预防药物将减少吸烟者/以前吸烟者患肺癌的机会，从而直接降低死亡率。

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.