Chemoprevention of Pancreatic Cancer by Capsaicin

主要调查者：Sriastava，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， 确诊后中位生存期不到6个月。它是最具攻击性的人类之一 恶性肿瘤的预后极差，因此提供了一个实验和临床挑战。 辣椒素对胰腺癌疗效进行详细临床前评估的理论基础 来源于我们来自体外和异种移植研究的坚实的初步数据。我们向人类展示了 胰腺癌细胞株ASPC-1和BxPC-3对辣椒素的生长抑制高度敏感。 有趣的是，来自正常胰腺或永生化正常胰腺的腺泡细胞的活性 辣椒素对人胰腺导管上皮细胞(HPDE-6)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可取的 以潜在的癌症预防或治疗剂为特征的。我们的结果还表明， 辣椒素的生长抑制作用与(1)细胞内反应水平升高有关 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，Survivin的下调和caspase-3级联的激活 这最终会诱导ASPC-1和BxPC-3细胞的凋亡，但不会诱导腺泡细胞的凋亡。此外, 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。 反映了由辣椒引发的细胞内氧化还原的有效变化 化合物。此外，我们还发现，口服辣椒素显著抑制了小鼠的生长。 无明显毒性的ASPC-1胰腺癌裸鼠移植瘤。肿瘤得自 辣椒素处理的小鼠Bax表达增加，胞浆细胞色素c，裂解 Caspase-3，降低有丝分裂活性，增加细胞凋亡。我们的结果还表明，辣椒素 增强吉西他滨对胰腺癌细胞的生长抑制作用。在基础上建设 这些有希望的数据，我们假设辣椒素可以有效地延缓胰腺 致癌，并通过一种有效的抗癌作用 氧化应激的不同诱导和调控导致JNK激活和 细胞凋亡的线粒体死亡途径。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 丝裂原调节和应激调节的信号转导通路的激活 辣椒素引起的氧化失衡；(3)辣椒素对心肌细胞活性的影响 线粒体死亡途径，以及(4)探讨辣椒素的防治作用。 裸鼠和KrasG12D转基因小鼠胰腺上皮内瘤变模型的建立 (Panins)及其生物利用度和药代动力学。成功完成这项工作 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.