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

描述（由申请人提供）：目前针对胰腺癌（PanCA）的治疗方法不足且疗效有限。因此，有一个巨大的未满足的需求，开发新的有效的化合物，选择性靶向肿瘤细胞。虽然天然产物被公认为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在胰腺癌中的潜在预防/治疗作用。我们从黄柏树皮中发现了一种天然化合物“NexrutineR”（Nx），它可以抑制胰腺癌细胞的生长，并通过产生活性氧（ROS）诱导细胞凋亡和自噬。此外，观察到的细胞毒性作用是肿瘤细胞特异性的。Nx降低了两个关键氧化还原调节的转录因子的水平和活性，这些转录因子控制致癌信号，即NF？B和Stat3导致抗凋亡蛋白FLIP的调节。基于这些观察，我们假设Nx含有具有有效抗胰腺癌活性的新型生物活性化合物。我们将验证Nx及其生物活性化合物通过一种新机制起作用的假设，在这种机制中，两种氧化还原调节的转录因子(Stat3和NF？B)导致肿瘤细胞特异性程序性死亡的调节。这一假设将在以下具体目标中得到解决：1 .确定人类胰腺癌细胞系面板上程序性细胞死亡过程与nx诱导的氧化应激之间的串扰机制；2：通过胰腺癌临床前动物模型证明，程序性细胞死亡过程和氧化应激之间的串扰中断可阻断或延迟肿瘤生长；3：利用细胞培养模型探讨Nx活性成分Palmatine重现Nx诱导生物活性的能力；4：通过胰腺癌临床前动物模型，评估Palmatine对程序性细胞死亡过程和氧化应激之间的串扰的破坏阻断或延迟肿瘤生长。Nx在肿瘤细胞中具有抗肿瘤活性，而在正常细胞中具有低毒性或无毒性，是一种很有前景的药物。这些研究将为制定针对胰腺癌的替代和补充药物策略提供合理的依据。

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.