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: 8627594
• 负责人: A.R.M. Ruhul Amin
• 金额: $ 7.57万
• 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/8627594
• 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年在美国估计有221，130例新发病例和156，940例死亡。尽管传统的外科手术、放疗和化疗取得了进展，但肺癌的5年生存率几乎保持不变，低于15%。肺癌死亡率可以通过实施化学预防策略来降低，这些策略可以逆转或阻止癌前病变的进展。激活细胞凋亡途径以消除癌前病变细胞是化学预防的重要途径。此外，在整个疾病进展过程中失活的肿瘤抑制途径的重新激活对于开发有效的化学预防策略是重要的。AKT的激活是肺癌中常见的几种致癌基因突变（如EGFR、KRAS、PTEN、PI 3 KCA等）下游的关键组成部分。我们假设肿瘤抑制因子FOXO通路通过激活AKT的磷酸化而失活，而不是缺失或突变。因此，可以通过灭活AKT来重新激活FOXO途径并同时激活其他凋亡途径（例如死亡受体介导的凋亡）的药剂可能是有效的化学预防剂。在过去的几十年中，广泛的临床前研究已经证明姜黄素具有很强的化学预防潜力，这使得这种药物进入临床试验。然而，低效力和差的生物利用度是关键挑战。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，修改递送系统或鉴定与天然姜黄素显示协同作用的试剂。我们发现，合成的姜黄素类似物FLLL-12对肺癌细胞系显示出5-10倍的效力，并激活Bim，其是AKT-FOXO信号传导的下游促凋亡效应物，沿着AKT的失活。同时，FLLL-12激活DR 5-caspase 8凋亡途径。由于FLLL-12激活内源性和外源性途径的生物标志物，因此我们假设FLLL-12是一种新型无毒药物，其靶向AKT-FOXO- Bim和DR 5-caspase 8途径对肺肿瘤发生的化学预防功效。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诱导的内在凋亡机制;（2）研究DR 5通路以了解外在（caspase 8介导的）凋亡;（3）研究FLLL-12在小鼠中的体内功效和生物利用度。我们预计， 研究将确定FLLL-12作为预防和控制肺癌生长的机制为基础的代理。这将确定其在临床前小鼠模型中的体内功效。因此，委员会认为， 这项试验研究的完成将有助我们进一步发展这种化合物，以应用于预防肺癌的临床用途。

项目成果

FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway.

• DOI: 10.1016/j.canlet.2015.04.017
• 发表时间: 2015-07-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Haque, Abedul;Rahman, Mohammad A.;Fuchs, James R.;Chen, Zhuo Georgia;Khuri, Fadlo R.;Shin, Dong M.;Amin, A. R. M. Ruhul
• 通讯作者: Amin, A. R. M. Ruhul