Pancreatic Cancer: Crocetin as a Novel Therapeutic Approach

胰腺癌：藏红花酸作为一种新的治疗方法

基本信息

批准号：
8507174
负责人：
ANIMESH DHAR
金额：
$ 24.68万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507174
关键词：
Acetylation Acids Address Affect Animal Model Antimitotic Agents Antineoplastic Agents Apoptosis BCL2 gene Cancer Model Carotenoids Caspase Cell Culture System Cell Cycle Cell Proliferation Chemopreventive Agent Drug Kinetics Effectiveness Epidermal Growth Factor Receptor Esters Event Fluorouracil Gene Proteins Goals Growth High Pressure Liquid Chromatography Histone Acetylation Histone Deacetylase Histones Human Impairment In Vitro Induction of Apoptosis Inhibition of Apoptosis Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Matrix Metalloproteinases Mediating Molecular Mus Neoplasm Metastasis Pancreatic Adenocarcinoma Patients Phase I Clinical Trials Phenotype Phosphorylation Preparation Regulation Saffron Signal Pathway Signal Transduction Testing Therapeutic Agents Xenograft Model Xenograft procedure antitumor agent cell growth conventional therapy crocetin gemcitabine gemzar histone modification in vitro Model in vivo in vivo Model liquid chromatography mass spectrometry migration mouse model novel novel therapeutic intervention pancreatic cancer cells tumor growth tumorigenesis tumorigenic

Acetylation Acids Address Affect Animal Model Antimitotic Agents Antineoplastic Agents Apoptosis BCL2 gene Cancer Model Carotenoids Caspase Cell Culture System Cell Cycle Cell Proliferation Chemopreventive Agent Drug Kinetics Effectiveness Epidermal Growth Factor Receptor Esters Event Fluorouracil Gene Proteins Goals Growth High Pressure Liquid Chromatography Histone Acetylation Histone Deacetylase Histones Human Impairment In Vitro Induction of Apoptosis Inhibition of Apoptosis Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Matrix Metalloproteinases Mediating Molecular Mus Neoplasm Metastasis Pancreatic Adenocarcinoma Patients Phase I Clinical Trials Phenotype Phosphorylation Preparation Regulation Saffron Signal Pathway Signal Transduction Testing Therapeutic Agents Xenograft Model Xenograft procedure antitumor agent cell growth conventional therapy crocetin gemcitabine gemzar histone modification in vitro Model in vivo in vivo Model liquid chromatography mass spectrometry migration mouse model novel novel therapeutic intervention pancreatic cancer cells tumor growth tumorigenesis tumorigenic

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项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most lethal malignancies in humans and there is no effective conventional treatment available for the cure of patients with pancreatic cancer. Crocetin, a carotenoid molecule isolated from saffron, has been demonstrated recently by our laboratory to have potent antimitotic effects both in in vitro and in vivo pancreatic cancer models. Commercial crocetin is a mixture of crocetinic acid and crocetin esters. We have recently fractionated commercial crocetin using preparative HPLC, and demonstrated that crocetinic acid is the most active component. The goal of this proposal is to identify all of the active components in crocetin, and determine the signaling mechanisms, responsible for inducing cellular proliferation and tumorigenesis of pancreatic adenocarcinoma that are impaired by purified crocetin components. Our central hypothesis is that crocetin inhibits cellular proliferation and stimulates apoptosis signaling pathways due to the impairment of histone modifications in pancreatic adenocarcinoma. The long term goal is to develop crocetin as therapeutic and chemopreventive agent. To test this hypothesis, four specific aims are proposed. Aim 1 (a): To purify, identify, and characterize the active components present in commercial preparations of crocetin. Aim 1 (b): To determine the pharmacokinetics of crocetin in pancreatic cancer in in vitro and in vivo models. Aim 2 : To determine purified crocetin-mediated regulation of i) histone modifications by acetylation, ii) inhibition of proliferation and iii) stimulation of apoptosis using in vitro pancreatic cancer models. The status of migration and invasion will be investigated in in vitro models. Aim 3: To determine purified crocetin mediated regression of pancreatic cancer in a xenograft mouse model. Aim 4: To determine whether purified crocetin will enhance the efficacy of conventional chemothrapeutic agents (gemcitabine [Gemzar] and/or 5-FU [Fluorouracil]) in impairing cell proliferation and the induction of apoptosis of pancreatic cancer cells in in vitro and in vivo models.. This is the first study to evaluate the effectiveness of novel crocetin in pancreatic cancer. This proposal will provide further evidence to justify and enocourage Phase I clinical trials using crocetin.

描述（由申请人提供）：胰腺癌是人类最致命的恶性肿瘤之一，并且没有有效的常规治疗可用于治愈胰腺癌患者。最近，我们的实验室证明了从藏红花中分离出的类胡萝卜素分子，在体外和体内胰腺癌模型中都具有有效的抗魔法作用。商业凸蛋白是鳄鱼酸和鳄鱼酯的混合物。我们最近使用制备HPLC对商业凸素进行了分级，并证明了叶酸是最活跃的成分。该提案的目的是识别凸蛋白中的所有活性成分，并确定信号传导机制，负责诱导细胞增殖和胰腺腺癌的肿瘤发生，这些腺癌受到纯化的crocecetin成分受损。我们的中心假设是，凸蛋白抑制细胞增殖并刺激胰腺腺癌中组蛋白修饰的损害，刺激细胞凋亡信号通路。长期目标是发展为治疗和化学预防剂。为了检验这一假设，提出了四个具体目标。目标1（a）：净化，识别和表征凸蛋白商业制剂中存在的活性成分。 AIM 1（b）：确定体外和体内模型中胰腺癌中凸蛋白的药代动力学。目标2：确定纯化的凸蛋白介导的调节I）通过乙酰化对组蛋白修饰的调节，ii）抑制增殖和iii）使用体外胰腺癌模型刺激凋亡。迁移和入侵状态将在体外模型中进行研究。目标3：确定异种移植小鼠模型中纯化的凸蛋白介导的胰腺癌回归。目的4：确定纯化的凸蛋白是否会增强常规化学施抗性剂（吉西他滨[gemzar]和/或5-Fu [氟尿嘧啶]）在损害细胞增殖中的功效，并诱导胰腺癌细胞的胰腺癌细胞的凋亡诱导，这是玻璃体和体内癌症中的首次研究。该提案将提供进一步的证据，以证明使用凸蛋白进行I期临床试验的合理性。