Targeting both intrinsic and extrinsic apoptosis by FLLL-12 in lung cancer

FLLL-12 靶向肺癌中的内在和外在细胞凋亡

• 批准号: 8512434
• 负责人: A.R.M. Ruhul Amin
• 金额: $ 7.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512434
• 关键词: A/J Mouse; Antineoplastic Agents; Apoptosis; Apoptotic; Attention; BCL2 gene; Biological Availability; Biological Markers; Butanones; Cancer cell line; Carcinogens; Cell Survival; Cessation of life; Chemoprevention; Chemopreventive Agent; Cleaved cell; Clinical; Clinical Trials; Curcumin; Cytoplasm; Data; Development; Diet; Disease; Disease Progression; Dose; Down-Regulation; Drug Kinetics; EGFR inhibition; Epidermal Growth Factor Receptor; Epithelial; Exhibits; Genetic; Growth; Human; Incidence; KRAS2 gene; Lesion; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mitochondria; Modification; Molecular Target; Mus; Mutation; New Agents; Oncogenic; Operative Surgical Procedures; PTEN gene; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Phosphorylation; Pilot Projects; Premalignant; Prevention; Preventive; Proto-Oncogene Proteins c-akt; Radiation therapy; Regimen; Role; Safety; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Smoker; Spices; Survival Rate; System; TNFRSF10B gene; Testing; Time; Tissues; Tobacco-Associated Carcinogen; Toxic effect; Tumeric; Tumor Suppressor Proteins; United States; Up-Regulation; analog; base; cancer cell; cancer prevention; cancer therapy; caspase-8; cell growth; chemotherapy; clinical application; cytochrome c; design; efficacy testing; fruits and vegetables; high risk; improved; in vivo; lung cancer prevention; lung carcinogenesis; lung tumorigenesis; mortality; mouse model; mutant; novel; pre-clinical; pre-clinical research; promoter; public health relevance; receptor; screening; small molecule; transcription factor; tumor

DESCRIPTION (provided by applicant): Lung cancer is the deadliest of all malignancies with an estimated 221,130 new cases and 156,940 deaths in the year 2011 in the United States. Despite advances in conventional surgical procedures, radiotherapy, and chemotherapy, the 5 year survival rate for lung cancer remains almost unchanged, at less than 15%. Mortality from lung cancer could be reduced through the implementation of chemopreventive strategies that can reverse or impede the progression of pre-malignant disease. Activation of apoptotic pathways to eliminate pre- malignant cells is an important approach for chemoprevention. Moreover, reactivation of the tumor suppressor pathways which are inactivated throughout disease progression is important to develop effective chemopreventive strategies. Activation of AKT is a critical component downstream of several driver oncogenic mutations frequently found in lung cancers such as EGFR, KRAS, PTEN, PI3KCA, etc. We hypothesize that the tumor suppressor FOXO pathway is inactivated through phosphorylation by activated AKT rather than deletion or mutation. Therefore, agents that could reactivate the FOXO pathway by inactivating AKT and simultaneously activate other apoptotic pathways, such as death receptor-mediated apoptosis, might be effective chemopreventive agents. Extensive preclinical research over the last several decades has demonstrated that curcumin has strong potential for chemoprevention, which brought this agent into clinical trials. However, low potency and poor bioavailability are critical challenges. To circumvent these problems, several approaches are being undertaken, such as synthesis of more potent analogs, modification of the delivery system or identification of agents that show synergy with natural curcumin. We found that the synthetic curcumin analog FLLL-12 shows 5-10-fold more potency against lung cancer cell lines and activates Bim, a downstream pro-apoptotic effector of AKT-FOXO signaling along with inactivation of AKT. At the same time, FLLL-12 activates the DR5-caspase 8 apoptotic pathway. Since FLLL-12 activates biomarkers of both intrinsic and extrinsic pathways, we hypothesize that FLLL-12 is a novel non-toxic agent that targets the AKT-FOXO- Bim and DR5-caspase 8 pathways in its chemopreventive efficacy against lung tumorigenesis. To test our hypothesis, we have designed three specific aims: (1) to study the mechanism of intrinsic apoptosis induced by FLLL-12; (2) to investigate the DR5 pathway to understand extrinsic (caspase 8-mediated) apoptosis; and (3) to study the in vivo efficacy and bioavailability of FLLL-12 in mice. We anticipate that this proposed study will identify FLLL-12 as a mechanism-based agent for the prevention and control of lung cancer growth. This will establish its in vivo efficacy in a pre-clinical mouse model. Accordingly, completion of this pilot study would help us to further develop this compound for clinical application for lung cancer prevention.

描述（由申请人提供）：肺癌是所有恶性肿瘤中最致命的，2011年美国估计有221,130例新发病例和156,940例死亡。尽管传统的外科手术、放疗和化疗都取得了进步，但肺癌的5年生存率几乎没有变化，仍低于15%。通过实施能够逆转或阻碍恶性前期疾病进展的化学预防战略，可以降低肺癌死亡率。激活凋亡通路以消除癌前细胞是化学预防的重要途径。此外，在疾病进展过程中失活的肿瘤抑制通路的重新激活对于制定有效的化学预防策略非常重要。AKT的激活是肺癌中常见的几种驱动致癌突变（如EGFR、KRAS、PTEN、PI3KCA等）下游的关键成分。我们假设肿瘤抑制因子FOXO通路是通过激活AKT的磷酸化而非缺失或突变而失活的。因此，能够通过灭活AKT来重新激活FOXO通路，同时激活其他凋亡通路（如死亡受体介导的凋亡）的药物可能是有效的化学预防药物。在过去的几十年里，大量的临床前研究表明，姜黄素具有很强的化学预防潜力，这使这种药物进入了临床试验。然而，效力低和生物利用度差是关键的挑战。为了避免这些问题，正在采取几种方法，例如合成更有效的类似物，修改递送系统或确定与天然姜黄素具有协同作用的药物。我们发现，合成姜黄素类似物FLLL-12对肺癌细胞系的效力提高了5-10倍，并激活了AKT- foxo信号传导的下游促凋亡效应物Bim，同时使AKT失活。同时，FLLL-12激活DR5-caspase 8凋亡通路。由于FLLL-12激活了内在和外在途径的生物标志物，我们假设FLLL-12是一种新的无毒药物，其针对AKT-FOXO- Bim和DR5-caspase 8途径的化学预防肺肿瘤发生的功效。为了验证我们的假设，我们设计了三个具体目标：(1)研究FLLL-12诱导细胞内生性凋亡的机制；(2)研究DR5通路以了解外源性（caspase 8介导的）细胞凋亡；(3)研究FLLL-12在小鼠体内的药效和生物利用度。我们期待这一提议