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

基本信息

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
项目类别：
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

项目摘要

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。尽管传统手术、放疗和化疗取得了进步，但肺癌的 5 年生存率几乎没有变化，仍低于 15%。通过实施可以逆转或阻止癌前疾病进展的化学预防策略，可以降低肺癌死亡率。激活凋亡途径以消除癌前细胞是化学预防的重要方法。此外，在疾病进展过程中失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）下游的关键组成部分。我们假设肿瘤抑制因子 FOXO 通路是通过激活的 AKT 磷酸化而不是缺失或突变而失活的。因此，能够通过灭活 AKT 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细胞凋亡）的药物可能是有效的化学预防剂。过去几十年的广泛临床前研究表明，姜黄素具有强大的化学预防潜力，这使得该药物进入了临床试验。然而，效力低和生物利用度差是严峻的挑战。为了解决这些问题，人们正在采取多种方法，例如合成更有效的类似物、改进递送系统或鉴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 Bim（AKT-FOXO 信号传导的下游促凋亡效应器）以及 AKT 失活。同时，FLLL-12 激活 DR5-caspase 8 凋亡途径。由于 FLLL-12 激活内在和外在途径的生物标志物，我们假设 FLLL-12 是一种新型无毒药物，其针对 AKT-FOXO-Bim 和 DR5-caspase 8 途径，具有针对肺部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诱导内源性细胞凋亡的机制； (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在小鼠体内的功效和生物利用度。我们预计这一提议研究将确定 FLLL-12 作为预防和控制肺癌生长的基于机制的药物。这将在临床前小鼠模型中确定其体内功效。因此，这项试点研究的完成将有助于我们进一步开发这种化合物，用于预防肺癌的临床应用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

FLLL12 通过不依赖 p53/p73 但依赖死亡受体 5 的途径诱导肺癌细胞凋亡。

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

Preclinical In Vitro, In Vivo, and Pharmacokinetic Evaluations of FLLL12 for the Prevention and Treatment of Head and Neck Cancers.

FLLL12 用于预防和治疗头颈癌的临床前体外、体内和药代动力学评估。