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。西红花酸是一种从紫茎泽兰中分离出来的类胡萝卜素分子，我们的实验室最近已经证明它在体外和体内胰腺癌模型中都具有有效的抗有丝分裂作用。商业藏红花酸是藏红花酸和藏红花酸酯的混合物。最近，我们已经分馏的商业藏红花酸使用制备HPLC，并证明，藏红花酸是最有效的成分。本提案的目的是鉴定藏红花酸中的所有活性成分，并确定负责诱导胰腺癌细胞增殖和肿瘤发生的信号传导机制，这些细胞增殖和肿瘤发生被纯化的藏红花酸成分损害。我们的中心假设是，藏红花酸抑制细胞增殖，并刺激细胞凋亡信号通路，由于组蛋白修饰在胰腺癌的损害。长期目标是开发西红花酸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、鉴定和表征西红花酸商业制剂中存在的活性成分。目的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。目标二：使用体外胰腺癌模型确定纯化的藏红花素介导的i）通过乙酰化进行的组蛋白修饰、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。目的3：在异种移植小鼠模型中确定纯化的藏红花酸介导的胰腺癌消退。目标4：在体外和体内模型中，确定纯化西红花酸是否会增强常规化疗药物（吉西他滨[健择]和/或5-FU [氟尿嘧啶]）在损害胰腺癌细胞增殖和诱导细胞凋亡方面的疗效。这是第一项评估新型西红花酸在胰腺癌中有效性的研究。这一建议将提供进一步的证据来证明和鼓励使用西红花酸的I期临床试验。 公共卫生相关性：胰腺癌是最致命的恶性肿瘤之一，目前尚无有效的常规治疗方法。这一探索性的RO-1提案将为开发一种新的藏红花酸化合物提供希望，该化合物来源于西红花苷，用于与已知的抗癌药物一起治疗胰腺癌。

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.