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Piperlongumine as a Novel Radiosensitizer for Lung Cancer

Piperlongumine 作为肺癌的新型放射增敏剂

基本信息

批准号：
9017962
负责人：
Melpo Christofidou-Solomidou
金额：
$ 16.71万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017962
关键词：
Adverse effects Antioxidants Biological Assay Botanicals Cancer Etiology Cancer Patient Capsicum Cell Death Cell Survival Cell division Cells Cessation of life Chest Communities DNA Damage DNA Double Strand Break DNA biosynthesis Data Development Diet Dose Effectiveness Fruit Gamma Rays Genes Genetic Transcription Genotype Goals Health Human Hypoxia Hypoxia Inducible Factor In Vitro Jaborandi Pepper Knowledge Lead Literature Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mission Molecular Mus Natural Products Normal Cell Normal tissue morphology Plants Property Public Health Radiation Radiation Tolerance Radiation Toxicity Radiation therapy Radiation-Sensitizing Agents Radioprotection Radiosensitization Reactive Oxygen Species Research Resistance Response Elements Role Solid Neoplasm Structure of parenchyma of lung Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Undifferentiated United States Vascular blood supply Work base cancer cell cancer radiation therapy cancer therapy cell killing cell transformation cell type effective therapy efficacy testing improved in vivo in vivo Model innovation irradiation mortality mouse model neoplastic cell novel novel strategies outcome forecast protective effect radiosensitizing response therapy development therapy resistant transcription factor treatment planning tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Although over half of all lung cancer patients receive radiation therapy as part of their treatment plan, the therapeutic window of radiation is quite small, and it is difficult to deliver tumoricidal doses of radiation without the development of severe adverse effects in the nearby normal tissues. An agent that could protect healthy lung tissue from radiation toxicity and at the same time sensitize lung cancer tissue to radiation therapy, would be a major advance in the treatment of lung cancer, the leading cause of cancer deaths in the United States. The long term goal for this research is to develop clinically-useful, natural product-based agents that improve treatment for cancer. The objective for this application is to establish the dual action of a natural product as both a tumor cell radiosensitizr and a normal cell radioprotector by determining its mechanisms of action and therapeutic efficacy in lung cancer radiotherapy. The central hypothesis is that the natural product PPLGM sensitizes tumor cells to radiation-induced cell death through inhibition of HIF2a and induction of ROS, and protects healthy cells from radiation by enhancing their antioxidant response. To test the central hypothesis, two Specific Aims are proposed: 1) Establish the mechanisms for PPLGM-induced lung cancer cell radiosensitization and healthy lung cell radioprotection in vitro; and 2) Evaluate the therapeutic efficacy of PPLGM for lung cancer radiosensitization and healthy lung cell radioprotection in vivo. For the first aim, functional assays will be performed t identify the lung cancer cell genotypes for which PPLGM is a radiosensitizer and the healthy lung cell types for which PPLGM is a radioprotector. Mechanistic studies will be done to evaluate the involvement of HIF2a in PPLGM-induced ROS, DNA damage, and cell death for lung cancer cells, as well as transcriptional targets of the hypoxic and antioxidant responses in lung cancer and healthy lung cells. For the second aim, the radiosensitizing effects of PPLGM on lung tumors will be established in a mouse model. Additionally, the radioprotective role of PPLGM will be evaluated in a mouse model of thoracic radiation-induced pneumonopathy both short-term (1 month) and long-term (4 months). The approach is innovative because it uses a novel dietary agent that shows potent anti-cancer effects with protective effects in healthy tissues for the first time in the context of lung radiotherapy. The proposed research is significan because it is expected to advance the field of radiation therapy by development of a more effective treatment for lung cancer. The results from this project are also expected to expand understanding of how natural products act as radiosensitizers for cancer cells and, at the same time, radioprotectors for healthy cells. Such knowledge has the potential to change the field of radiation therapy and result in more effective treatment for many cancers.

描述(申请人提供)：尽管超过一半的肺癌患者接受放射治疗作为其治疗计划的一部分，但放射治疗的治疗窗口相当小，而且很难在不对附近正常组织产生严重不良反应的情况下提供杀瘤剂量的辐射。一种可以保护健康的肺组织免受辐射毒性，同时使肺癌组织对放射治疗敏感的药物，将是肺癌治疗的重大进步，肺癌是美国癌症死亡的主要原因。这项研究的长期目标是开发临床上有用的、以天然产品为基础的药物，以改善癌症的治疗。本应用的目的是通过确定天然产物在肺癌放射治疗中的作用机制和治疗效果，确定其作为肿瘤细胞放射增敏剂和正常细胞辐射保护剂的双重作用。中心假设是，天然产物PPLGM通过抑制HIF2A和诱导HIF2A使肿瘤细胞对辐射诱导的细胞死亡敏感。 ROS，并通过增强细胞的抗氧化反应来保护健康细胞免受辐射。为了验证这一中心假设，我们提出了两个具体的目标：1)在体外建立PPLGM诱导的肺癌细胞放射增敏和健康肺细胞辐射保护的机制；2)在体内评价PPLGM对肺癌放射增敏和健康肺细胞辐射保护的治疗效果。对于第一个目的，将进行功能分析，以确定PPLGM作为放射增敏剂的肺癌细胞基因型和PPLGM作为放射防护剂的健康肺细胞类型。将进行机制研究，以评估HIF2A在PPLGM诱导的肺癌细胞ROS、DNA损伤和细胞死亡中的作用，以及肺癌和健康肺细胞缺氧和抗氧化反应的转录靶点。对于第二个目的，将在小鼠模型上建立PPLGM对肺癌的放射增敏作用。此外，PPLGM的辐射防护作用将在短期(1个月)和长期(4个月)胸部放射性肺炎的小鼠模型中进行评估。这种方法是创新的，因为它使用了一种新型的膳食剂，在肺部放射治疗的背景下首次在健康组织中显示出强大的抗癌效果和保护作用。这项研究具有重要意义，因为它有望通过开发一种更有效的肺癌治疗方法来推动放射治疗领域的发展。该项目的结果还有望扩大对天然产品如何作为癌细胞的辐射增敏剂，同时作为健康细胞的辐射防护剂的理解。这些知识有可能改变放射治疗领域，并导致对许多癌症进行更有效的治疗。