Oxidative stress and programmed death pathways: Cross talk in pancreatic cancer

描述(由申请人提供)：目前治疗胰腺癌的方法不够充分，疗效有限。因此，对选择性靶向肿瘤细胞的新型有效化合物的开发有着巨大的未得到满足的需求。虽然天然产物被公认为治疗包括癌症在内的各种疾病的药物来源，但很少有研究系统地探讨天然产物对胰腺癌潜在的预防/治疗益处的作用。我们发现了一种从黄柏树皮中分离出来的天然化合物NexrutineR(Nx)，它能抑制胰腺癌细胞的生长，并通过产生活性氧(ROS)来诱导细胞凋亡和自噬。此外，观察到的细胞毒作用是针对肿瘤细胞的。NX降低了两个关键的氧化还原调节的转录因子的水平和活性，这两个转录因子控制着致癌信号，即NF？B和STAT3，导致了抗凋亡蛋白翻转的调节。基于这些观察，我们推测NX含有新的生物活性化合物，具有很强的抗胰腺癌活性。我们将验证NX及其生物活性化合物通过一种新的机制发挥作用的假设，在该机制中，两个氧化还原调节转录因子(STAT3和NF？B)的翻转调节导致肿瘤细胞特异性程序性细胞死亡的调节。这一假说将具体达到以下目标：1：确定细胞程序性死亡过程和NX诱导的氧化应激之间的串扰机制；2：通过临床前胰腺癌动物模型证明细胞程序性死亡过程和氧化应激之间的串扰阻断或延迟肿瘤的生长；3：通过细胞培养模型探讨NX的生物活性成分Palmatine概括NX诱导的生物活性的能力；4：使用临床前胰腺癌动物模型评估Palmatine对细胞程序性死亡过程和氧化应激之间的串扰的阻断或延缓肿瘤的生长。NX是一种很有前途的抗肿瘤活性药物，在正常细胞中毒性很低甚至没有。这些研究将为开发针对胰腺癌的替代和补充药物策略提供合理的基础。

DESCRIPTION (provided by applicant): Current therapies against pancreatic cancer (PanCA) are inadequate and limited in efficacy. Therefore there is a huge unmet need for development of novel effective compounds that selectively target tumor cells. Although natural products are well recognized as sources of drugs for various diseases including cancer, very few studies systematically explored the role of natural products for their potential preventive/therapeutic benefit in pancreatic cancer. We have discovered a natural compound called "NexrutineR" (Nx) isolated from the bark of Phellodendron amurense that inhibits pancreatic cancer cell growth and induces apoptosis and autophagy through production of reactive oxygen species (ROS). Further the observed cytotoxic effects are specific to tumor cells. Nx decreased levels and activity of two key redox-regulated transcription factors that control oncogenic signaling namely NF?B and Stat3 that results in modulation of anti-apoptotic protein FLIP. Based on these observations we postulate that Nx contains novel bioactive compounds with potent anti-pancreatic cancer activity. We will test the hypothesis that Nx and its bioactive compound works through a novel mechanism in which FLIP regulation by two redox-regulated transcription factors (Stat3 and NF?B) leads to modulation of tumor cell specific programmed cell death. This hypothesis will be addressed in following specific aims: 1: Determine the mechanism of cross talk between programmed cell death processes and Nx-induced oxidative stress ina panel of human pancreatic cancer cell lines; 2: Demonstrate that the disruption of cross talk between programmed cell death processes and oxidative stress blocks or delays tumor growth using preclinical animal models of pancreatic cancer; 3: Explore the ability of Palmatine, a bioactive component of Nx recapitulate Nx-induced biological activities using cell culture models; 4: Evaluate that the disruption of cross talk between programmed cell death processes and oxidative stress using Palmatine blocks or delays tumor growth using preclinical animal models of pancreatic cancer. Nx is a promising agent for its anti-tumorigenic activity in cancer cells wit low to no toxicity in normal cells. These studies will provide a rational basis for developing alternative and complementary medicinal strategies for targeting pancreatic cancer.