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Targeting ROS by a p53-activating agent for selective killing of cancer cells

p53 激活剂靶向 ROS 选择性杀死癌细胞

基本信息

批准号：
8433262
负责人：
SAM W LEE
金额：
$ 32.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433262
关键词：
A549 Address Adverse effects Affinity Chromatography Antioxidants Apoptosis Apoptotic Biochemical Bladder Breast Breast Cancer Model Cancer Cell Growth Cancer cell line Cell Death Cells Cessation of life Characteristics Chemotherapy-Oncologic Procedure Cisplatin Clinical Collaborations Combined Modality Therapy Cytotoxic Chemotherapy Cytotoxic agent DNA Damage Development Dose Drug Design Drug Discovery Groups Drug resistance Generations Genetic Transcription Genotoxic Stress Goals Histocompatibility Testing Human In Vitro Institutes Ionizing radiation Left Lung MAPK8 gene Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Mind Molecular Molecular Target Mouse Mammary Tumor Virus Mus Names Normal Cell Normal tissue morphology Noxae Organ Oxidative Stress Oxidative Stress Induction Paclitaxel Pathway interactions Pharmaceutical Preparations Phenotype Production Protein p53 Radiation therapy Radio Reactive Oxygen Species Research Resistance Role Signal Transduction System Testing Therapeutic Tissues Transgenic Mice Treatment Efficacy Tumorigenicity abstracting base cancer cell cancer therapy cell type chemical genetics chemotherapeutic agent chemotherapy cytotoxic design drug discovery in vivo insight interest irradiation killings melanoma mouse model neoplastic cell novel nutlin 3 pre-clinical promoter public health relevance research study response small molecule tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Abstract DNA damage-induced cell death through chemo-drugs is the most widely used strategy in cancer therapy. However, selectivity remains a great concern in cancer chemotherapy because DNA damaging drugs kill both cancer cells and the surrounding normal cells, which is an important cause of side effects during cancer chemotherapy, and severely limits current treatment regimes. Functional p53 deficiency is common in human tumors and contributes to an aggressive chemo- or radiotherapy-resistant phenotype, therefore providing a potential target for cancer therapy. Several attempts in recent years to restore wt- p53 activity have led to the identification of numerous p53 modulators. However, strategies mimicking p53 activated transcriptional responses in wt-p53 or p53-deficient tumors have yet to be explored. We carried out a high-throughput cell-based screen for small molecules that trigger a p53 target transcription in cancer cells. Among several candidates that elevate the amounts of p53 proteins, a naturally occurring novel p53 modulator, piperlongumine (PPLGM) is of most interest for this application because it selectively kills cancer cells in both p53-dependent and p53-independent ways, while leaving normal cells unaffected. This compound effectively increases basal levels of p53 protein and its proapoptotic targets. Furthermore, in vivo experiments demonstrate potent anti-tumor activities of this compound at low concentrations, which have no apparent adverse effects on normal organ and tissue function. We also identified significant elevation of reactive oxygen species (ROS) as a potential cancer cell specific mechanism of action for this compound. Therefore, targeting ROS could be a strategy to be developed to selectively kill cancer cells but not untransformed or normal cells by additional ROS production, because cancer cells possess a much higher basal level of ROS in comparison to normal cells. The main goal of this application is to understand the underlying mechanisms for the unusual selective effect of PPLGM in cancer cells in vitro and in vivo. A detailed understanding of the mechanism of action of this compound in both cancer cells and normal cells should provide novel insights into the target based selective therapeutic strategies against cancer, and may also warrant further testing in preclinical and clinical settings.

描述（由申请人提供）：摘要通过化疗药物引起的DNA损伤诱导的细胞死亡是癌症治疗中最广泛使用的策略。然而，在癌症化疗中，选择性仍然是一个很大的问题，因为DNA损伤药物杀死癌细胞和周围的正常细胞，这是癌症化疗期间副作用的重要原因，并严重限制了目前的治疗方案。功能性p53缺陷在人类肿瘤中很常见，并导致侵袭性化疗或放疗抗性表型，因此为癌症治疗提供了潜在的靶点。近年来恢复wt-p53活性的几次尝试已经鉴定出许多p53调节剂。然而，在野生型p53或p53缺陷型肿瘤中模拟p53激活的转录反应的策略还有待探索。我们进行了一项高通量的基于细胞的筛选，以寻找在癌细胞中触发p53靶转录的小分子。在提高p53蛋白量的几种候选物中，天然存在的新型p53调节剂piperlongumine（PPLGM）对于该应用最感兴趣，因为它以p53依赖性和p53非依赖性方式选择性地杀死癌细胞，同时使正常细胞不受影响。该化合物有效地增加了p53蛋白及其促凋亡靶点的基础水平。此外，体内实验证明该化合物在低浓度下具有有效的抗肿瘤活性，对正常器官和组织功能没有明显的不良影响。我们还确定了活性氧（ROS）的显着升高作为该化合物的潜在癌细胞特异性作用机制。因此，靶向ROS可能是一种待开发的策略，以通过额外的ROS产生来选择性地杀死癌细胞而不是未转化的细胞或正常细胞，因为癌细胞与正常细胞相比具有高得多的ROS基础水平。本申请的主要目标是了解PPLGM在体外和体内癌细胞中的不寻常选择性作用的潜在机制。对该化合物在癌细胞和正常细胞中的作用机制的详细了解应该为基于靶点的选择性抗癌治疗策略提供新的见解，并且还可以保证在临床前和临床环境中进行进一步的测试。