Chemoprevention of Pancreatic Cancer by Capsaicin

主要研究者：Srivastava，Sanjay K. 辣椒素对胰腺癌的化学预防作用 摘要 胰腺癌仍然是美国癌症相关死亡的第四大原因， 诊断后的中位生存期小于6个月。它是最具侵略性的人类之一 预后极差的恶性肿瘤，因此提供了实验和临床挑战。 辣椒素对胰腺癌疗效的详细临床前评价的基本原理 源于我们从体外和异种移植研究中获得的可靠的初步数据。我们发现人类 胰腺癌细胞系AsPC-1和BxPC-3对辣椒素的生长抑制高度敏感。 有趣的是，来自正常人胰腺或永生化正常胰腺的腺泡细胞的活力 人胰腺导管上皮（HPDE-6）细胞受辣椒素的影响最小。这些 结果特别令人鼓舞，因为选择性杀死癌细胞是一种理想的方法。 具有潜在的癌症预防剂或治疗剂的特征。我们的研究结果还表明， 辣椒素的生长抑制作用与（i）细胞内反应性蛋白水平升高有关， 氧物种（ROS），（ii）bax表达增加，（iii）导致线粒体去极化， 细胞色素c和AIF的释放，存活素的下调，以及半胱天冬酶-3级联的激活 最终诱导AsPC-1和BxPC-3细胞凋亡，但不诱导腺泡细胞凋亡。此外，本发明还提供了一种方法， 我们发现，辣椒素显著降低谷胱甘肽和硫氧还蛋白水平，并激活JNK， 胰腺癌细胞，反映了辣椒引发的细胞内氧化还原的强烈变化 化合物.此外，我们发现，口服辣椒素显着延缓生长， AsPC-1胰腺肿瘤裸鼠异种移植物，无明显毒性。肿瘤来源于 辣椒素处理的小鼠表现出增加的Bax表达，细胞质细胞色素c， caspase-3，减少有丝分裂活性和增加凋亡。我们的研究结果还表明， 增强吉西他滨在胰腺癌细胞中的生长抑制作用。基础上 这些有希望的数据，我们假设辣椒素可以有效地延缓胰腺炎， 致癌作用，也发挥有效的抗癌作用，对这种肿瘤类型，通过 氧化应激的差异诱导和调节导致JNK活化， 线粒体凋亡途径。为了验证这一假设，我们将：（1）阐明 辣椒素引发胰腺癌细胞氧化应激的机制，（2）研究 有丝分裂原和应激调节的信号转导通路的激活， 辣椒素诱导的氧化失衡，（3）确定辣椒素对激活 研究辣椒素对线粒体死亡途径的预防和治疗作用。 胰腺上皮内瘤变的无胸腺裸鼠和KrasG 12 D转基因小鼠模型 （PanINs）及其生物利用度和药代动力学。成功完成本 该项目将支持辣椒素的开发和临床应用，用于化学预防 胰腺癌

Principal Investigator: Srivastava, Sanjay K. CHEMOPREVENTION OF PANCREATIC CANCER BY CAPSAICIN Abstract Pancreatic cancer remains the fourth leading cause of cancer-related death in the United States with a median survival of less than 6 months following diagnosis. It is one of the most aggressive human malignancies with extremely poor prognosis, thus offering an experimental and clinical challenge. Rationale for a detailed pre-clinical evaluation of capsaicin for its efficacy against pancreatic cancer stems from our solid preliminary data from in vitro and xenograft studies. We showed that human pancreatic cancer cell lines AsPC-1 and BxPC-3 are highly sensitive to growth inhibition by capsaicin. Interestingly, the viability of acinar cells derived from normal human pancreas or immortalized normal human pancreatic ductal epithelial (HPDE-6) cells were minimally affected by capsaicin. These results are particularly encouraging because selective killing of cancer cells is a desirable characteristic of a potential cancer preventive or therapeutic agent. Our results also showed that growth inhibitory effect of capsaicin is associated with the (i) elevated levels of intracellular reactive oxygen species (ROS), (ii) increased expression of bax, (iii) leading to mitochondrial depolarization, release of cytochrome c and AIF, down regulation of survivin, and activation of caspase-3 cascade that eventually induces apoptosis in both AsPC-1 and BxPC-3 cells but not in acinar cells. In addition, we found that capsaicin significantly reduces glutathione and thioredoxin levels and activated JNK in pancreatic cancer cells, reflecting the potent alterations in intracellular redox triggered by the chili compound. Furthermore, we found that orally feeding capsaicin significantly retard the growth of AsPC-1 pancreatic tumor xenograft in nude mice with no discernible toxicity. Tumors obtained from capsaicin treated mice exhibited increased Bax expression, cytoplasmic cytochrome c, cleavage of caspase-3, reduced mitototic activity and increased apoptosis. Our results also showed that capsaicin enhances the growth suppressive effects of gemcitabine in pancreatic cancer cells. Building on these promising data, we hypothesize that capsaicin can effectively retard pancreatic carcinogenesis, and also exert potent anticancer effects against this tumor type, through a differential induction and modulation of oxidative stress leading to JNK activation and mitochondrial death pathway of apoptosis. To test this hypothesis we will: (1) Elucidate the mechanisms by which capsaicin triggers oxidative stress in pancreatic cancer cells, (2) Investigate the activation of mitogen- and stress-regulated signal transduction pathways in response to the oxidative imbalance induced by capsaicin, (3) Determine the effect of capsaicin on the activation of mitochondrial death pathway, and (4) Investigate the preventive and therapeutic effect of capsaicin in athymic nude mice and KrasG12D transgenic mice models of pancreatic intraepithelial neoplasia (PanINs) respectively and its bioavailability and pharmacokinetics. Successful completion of this project will support the development and clinical application of capsaicin for the chemoprevention of pancreatic cancer.