A new curcumin analogue with potent suppressive activity in pancreatic cancer

描述（由申请人提供）：胰腺癌中几种致癌途径典型地过表达和激活，包括AKT、信号转导和转录激活因子3（STAT 3）、Notch-1和NF-？B。有效的治疗剂可能需要表现出抑制这些途径的能力。STAT3、Notch-1、NF-？B和AKT途径是胰腺癌中激活的主要致癌途径之一。这四种致癌途径被认为在胰腺癌的生长、存活、侵袭、血管生成和其他功能中起关键作用，从而成为这种癌症的有吸引力的治疗靶点。我们建议评估GO-Y 030的抑制功效，GO-Y 030是一种新的更有效的膳食剂姜黄素类似物。我们在该提案中的初步结果首次证明，GO-Y 030在抑制胰腺癌细胞活力方面比姜黄素强约26-397倍，并且比cu细胞系更有效。我们还将研究STAT 3，AKT和Notch-1的表达是否可以挽救GO-Y 030在胰腺癌细胞中的抑制作用。在具体目标2中，我们将评估GO-Y 030在原位肿瘤模型中抑制PANC-1、MIA-PACA-2和BxPC-3胰腺癌细胞的抑制功效。胰腺癌是最严重的癌症类型之一，迫切需要开发更有效的胰腺癌治疗剂。我们提出的研究，如果成功，将提供一个有前途的潜力，使用GO-Y 030作为胰腺癌的新型治疗药物，最终目标是降低胰腺癌的死亡率，并延长健康生活的质量，为人们在这个国家和世界各地。公共卫生相关性：美国每年约有32，000人被诊断患有胰腺癌。胰腺外分泌部的癌症很少能治愈，总生存率低于4%。的. 胰腺癌治疗方法的改进本提案的目的是评估一种新的高效姜黄素类似物GO-Y 030在体外人胰腺癌细胞和小鼠原位肿瘤模型中的抑制功效。这些结果将提供GO-Y 030作为胰腺癌更有效治疗的潜在治疗剂的临床前活性

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