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年估计有221,130例新病例和156,940例死亡。尽管传统手术程序，放疗和化学疗法的进步，但肺癌的5年存活率几乎保持不变，不到15％。通过实施化学预防策略，可以扭转或阻碍恶性疾病的进展，可以降低肺癌的死亡率。消除恶性细胞的凋亡途径的激活是化学预防的重要方法。此外，在整个疾病进展中灭活的肿瘤抑制途径的重新激活对于制定有效的化学预防策略很重要。 AKT的激活是在肺癌中经常发现的几个驱动器致癌突变的关键成分，例如EGFR，KRAS，PTEN，PI3KCA等。我们假设我们假设肿瘤抑制FOXO途径是通过激活的AKT而不是消除磷酸化而不是磷酸化而不是消除磷酸化的。因此，可以通过灭活AKT并同时激活其他凋亡途径（例如死亡受体介导的凋亡）来重新激活FOXO途径的药物可能是有效的化学预防剂。在过去的几十年中，广泛的临床前研究表明，姜黄素具有强大的化学预防潜力，这将该药物带入了临床试验。但是，低效力和差的生物利用度是关键的挑战。为了解决这些问题，正在采用几种方法，例如合成更有效的类似物，修改输送系统或鉴定与天然姜黄素协同作用的药物。我们发现合成姜黄素模拟FLLL-12显示了针对肺癌细胞系的5-10倍效力，并激活BIM，BIM是Akt-Foxo信号的下游促凋亡效应子，以及Akt失活。同时，FLLL-12激活DR5-Caspase 8凋亡途径。由于FLLL-12激活了固有和外在途径的生物标志物，因此我们假设FLLL-12是一种新型的无毒剂，它靶向其在对肺肿瘤发生的化学预防效力中，靶向Akt-Foxo-BIM和DR5-Caspase 8途径。为了检验我们的假设，我们设计了三个特定的目的：（1）研究FLLL-12诱导的内在凋亡的机制； （2）研究DR5途径，以了解外部（caspase 8介导的）凋亡； （3）研究小鼠FLLL-12的体内功效和生物利用度。我们预计这提出了 研究将把FLLL-12识别为基于机制的预防和​​控制肺癌生长的药物。这将在临床前小鼠模型中确定其体内功效。因此， 这项试验研究的完成将有助于我们进一步开发这种预防肺癌临床应用的化合物。

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