A new curcumin analogue with potent suppressive activity in pancreatic cancer

描述(申请人提供)：几种致癌途径在胰腺癌中典型地过表达和激活，包括AKT、信号转导和转录激活因子3(STAT3)、Notch-1和NF-？B。有效的治疗药物可能需要表现出抑制这些途径的能力。STAT3、Notch-1、NF-β和AKT通路是胰腺癌中激活的主要致癌通路。这四条致癌途径被认为在胰腺癌的生长、存活、侵袭、血管生成等功能中发挥重要作用，因此成为治疗胰腺癌的重要靶点。我们建议评估GO-Y030的抑制效果，GO-Y030是一种新的更有效的膳食剂姜黄素类似物。我们在这项提案中的初步结果首次表明，GO-Y030在抑制胰腺癌细胞活性方面的效力大约是姜黄素的26-397倍，而且比铜细胞系更有效。我们还将检测STAT3、AKT和Notch-1的表达是否可以挽救GO-Y030对胰腺癌细胞的抑制作用。在特定目的2中，我们将评价GO-Y030对胰腺癌细胞PANC-1、MIA-PACA-2和BxPC-3的抑制作用。胰腺癌是最严重的癌症之一，迫切需要开发更有效的治疗胰腺癌的药物。我们提出的研究如果成功，将提供将GO-Y030作为一种新型胰腺癌治疗剂的前景，最终目标是降低胰腺癌的死亡率，并提高美国和世界各地人民的健康生活质量。与公共卫生相关：美国每年约有3.2万人被诊断出患有胰腺癌。胰腺外分泌癌很少治愈，总体存活率不到4%。这个。

DESCRIPTION (provided by applicant): Several oncogenic pathways are typical overexpressed and activated in pancreatic cancer, which include AKT, Signal Transducer and Activator of Transcription 3 (STAT3), Notch-1, and NF-?B. An effective therapeutic agent may need to exhibit the capacity to inhibit these pathways. STAT3, Notch-1, NF-?B, and AKT pathways are among the major oncogenic pathways activated in pancreatic cancer. These four oncogenic pathways are considered to play critical roles in growth, survival, invasion, angiogenesis, and other functions in pancreatic cancer and thereby emerged as attractive therapeutic targets for this cancer. We proposed to evaluate the inhibitory efficacy of GO-Y030, a new and more potent analogue of the dietary agent, curcumin. Our preliminary results in this proposal demonstrated for the first time that GO-Y030 is approximately 26-397 times more potent than curcumin in inhibiting pancreatic cancer cell viability as well as more potent than cu cell lines. We will also examine whether the expression of STAT3, AKT, and Notch-1 can rescue the inhibitory effects of GO-Y030 in pancreatic cancer cells. In specific aim 2, we will evaluate the inhibitory efficacy of GO-Y030 to suppress PANC-1, MIA-PACA-2, and BxPC-3 pancreatic cancer cells in orthotopic tumor model. Pancreatic cancer is one of the most serious types of cancer and there is a critical need to develop more effective therapeutic agents for pancreatic cancer. Our proposed studies, if successful, will provide a promising potential using GO-Y030 as a novel therapeutic agent for pancreatic cancer with the ultimate goal to reduce the mortality of pancreatic cancer and extending the quality of healthy life for people in this country and around the world. PUBLIC HEALTH RELEVANCE: Each year about 32,000 individuals in the United States are diagnosed with pancreatic cancer. Cancer of the exocrine pancreas is rarely curable and has an overall survival rate of less than 4%. The. itical need for better treatment approaches for pancreatic cancer. The objectives of this proposal are to evaluate the inhibitory efficacy of a new and highly potent curcumin analogue, GO-Y030 in human pancreatic cancer cells in vitro and in a mouse orthotopic tumor model. These results will provide the pre- clinical activities of GO-Y030 as a potential therapeutic agent for more effective treatment for pancreatic cancer