Pancreatic Cancer: Crocetin as a Novel Therapeutic Approach

描述（由申请人提供）：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用于治愈胰腺癌患者。Crocetin是一种从藏红花中分离出来的类胡萝卜素分子，最近我们的实验室在体外和体内胰腺癌模型中都证明了它具有强大的抗有丝分裂作用。商用藏红花素是藏红花酸和藏红花素酯的混合物。我们最近用制备型高效液相色谱分离了商业藏红花素，并证明藏红花酸是最有效的成分。本提案的目的是鉴定番石榴素中的所有活性成分，并确定信号机制，负责诱导细胞增殖和胰腺腺癌的肿瘤发生被纯化的番石榴素成分受损。我们的中心假设是，由于胰腺腺癌中组蛋白修饰的损伤，crocetin抑制细胞增殖并刺激凋亡信号通路。长期目标是发展克罗辛作为治疗和化学预防剂。为了验证这一假设，提出了四个具体目标。目的1 (a)：纯化、鉴定和表征西红花苷商业制剂中存在的有效成分。目的1 (b)：通过体外和体内模型确定西红花素在胰腺癌中的药代动力学。目的2：利用体外胰腺癌模型确定纯化藏红花素介导的i)组蛋白乙酰化修饰，ii)抑制增殖和iii)刺激细胞凋亡的调节。将在体外模型中研究其迁移和侵袭状况。目的3：在异种移植小鼠模型中确定纯化的红花素介导的胰腺癌消退。目的4：在体外和体内模型中，确定纯化的crocetin是否会增强常规化疗药物（吉西他滨[Gemzar]和/或5-FU[氟尿嘧啶]）在损害细胞增殖和诱导胰腺癌细胞凋亡方面的功效。这是第一个评估新型crocetin治疗胰腺癌有效性的研究。该提案将提供进一步的证据来证明和鼓励使用crocetin的I期临床试验。

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.