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：
8109729
负责人：
ANIMESH DHAR
金额：
$ 27.53万
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/8109729
关键词：
Acetylation Acids Address Affect Animal Model Antimitotic Agents Antineoplastic Agents Apoptosis Cancer Model Carotenoids 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 caspase-2 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

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most lethal malignancies and there is no effective conventional treatment in pancreatic cancer. This exploratory RO-1 proposal will offer a promise for developing a novel crocetin compound derived from saffron for therapy with known anticancer agents in pancreatic cancer.

描述（申请人提供）：胰腺癌是人类最致命的恶性肿瘤之一，目前尚无有效的常规治疗方法可以治愈胰腺癌患者。藏红花酸是一种从藏红花中分离出来的类胡萝卜素分子，我们的实验室最近证明它在体外和体内胰腺癌模型中具有有效的抗有丝分裂作用。商业藏花酸是藏花酸和藏花酸酯的混合物。我们最近使用制备型 HPLC 分离了商业藏花酸，并证明藏花酸是最活跃的成分。该提案的目标是鉴定藏红花酸中的所有活性成分，并确定信号传导机制，负责诱导纯化的藏红花酸成分损害的胰腺腺癌的细胞增殖和肿瘤发生。我们的中心假设是，藏红花酸由于胰腺腺癌中组蛋白修饰的受损而抑制细胞增殖并刺激细胞凋亡信号通路。长期目标是开发藏花酸作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)：纯化、鉴定和表征藏红花酸商业制剂中存在的活性成分。目标 1 (b)：在体外和体内模型中确定藏红花酸在胰腺癌中的药代动力学。目标 2：使用体外胰腺癌模型来确定纯化的藏花酸介导的 i) 组蛋白乙酰化修饰、ii) 增殖抑制和 iii) 细胞凋亡刺激的调节。将在体外模型中研究迁移和侵袭的状态。目标 3：确定纯化的藏花酸在异种移植小鼠模型中介导的胰腺癌消退。目标 4：确定纯化的藏花酸是否会增强传统化疗药物（吉西他滨 [Gemzar] 和/或 5-FU [氟尿嘧啶]）在体外和体内损害细胞增殖和诱导胰腺癌细胞凋亡的功效这是第一个评估新型藏花酸对胰腺癌有效性的研究。该提案将为证明和鼓励使用藏红花酸的 I 期临床试验提供进一步的证据。公众健康相关性：胰腺癌是最致命的恶性肿瘤之一，胰腺癌尚无有效的常规治疗方法。这项探索性的 RO-1 提案将为开发一种从藏红花中提取的新型藏红花酸化合物提供希望，用于用已知的抗癌药物治疗胰腺癌。