Pancreatic Cancer: Crocetin as a Novel Therapeutic Approach

描述(申请人提供)：胰腺癌是人类最致命的恶性肿瘤之一，目前还没有有效的常规治疗方法来治愈胰腺癌患者。藏红花素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都具有强大的抗有丝分裂作用。商业藏红花是藏红花酸和藏红花酸酯的混合物。我们最近用制备性高效液相色谱法对商品西红花素进行了分级，并证明了西红花酸是最有效的成分。该方案的目的是鉴定西红花素中的所有活性成分，并确定导致被纯化的西红花素成分损害的胰腺癌细胞增殖和肿瘤形成的信号机制。我们的中心假设是，由于组蛋白修饰的损伤，西红花酸在胰腺癌中抑制细胞增殖并刺激凋亡信号通路。长期目标是开发西红花酸作为治疗和化学预防药物。为了验证这一假设，本文提出了四个具体目标。目的1(A)：提纯、鉴定和鉴定商品制剂中存在的活性成分。目的1(B)：测定西红花酸在胰腺癌体内和体外的药代动力学。目的：利用体外胰腺癌模型，研究纯化的西红花酸对组蛋白乙酰化修饰、增殖抑制和细胞凋亡的调节作用。迁移和侵袭状态将在体外模型中进行研究。目的：观察纯化的西红花酸对小鼠胰腺癌的抑制作用。目的：确定纯化的西红花酸是否能增强传统化疗药物(吉西他滨[健择]和/或5-氟尿嘧啶[氟尿嘧啶])在体内外抑制胰腺癌细胞增殖和诱导细胞凋亡的作用。这是第一次评估新型西红花酸治疗胰腺癌的有效性的研究。这项建议将提供进一步的证据，证明并鼓励使用西红花素进行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.