β-榄香烯对放疗诱导的肺癌血管形成的作用和分子机制研究

项目名称： β-榄香烯对放疗诱导的肺癌血管形成的作用和分子机制研究

项目编号： No.81473452

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邹丽娟

作者单位： 大连医科大学

项目金额： 73万元

中文摘要： 抗肿瘤血管药协同放疗是提高肺癌放疗疗效的有效手段。放疗虽然可直接破坏肿瘤血管新生，但依赖骨髓来源肿瘤相关巨噬细胞（TAM）募集的血管形成，却成为放疗后残存、复发肿瘤重构血管的途径，其作用机制值得进一步探讨。新近研究表明在乏氧环境下，肺癌细胞和TAM细胞可能通过Prx-1激活的TLR4/NF-κB与HIF-1α间正反馈分子环路，诱导TAM的募集和M2表型的转化，促进肿瘤生成新的血管。我们前期也发现中药β-榄香烯对肺癌的放射增敏作用与抗肺癌血管生成有关，且增敏的靶点为HIF-1α、Prx-1。因此本课题旨在通过在放疗诱导的乏氧环境下，检测β-榄香烯和放疗对肺癌血管形成的作用以及Prx-1激活的TLR4/NF-κB与HIF-1α间正反馈分子环路影响，明确该正反馈分子环路是放疗诱导肺癌血管形成的重要机制和主要靶点，以期为开发抗血管靶向药物和中药β-榄香烯作为抗血管生成药物提高肺癌疗效提供理论依据。

中文关键词： β-榄香烯；放疗；肺癌；肿瘤血管形成；分子机制

英文摘要： The management of inhibiting tumor vessels is an effective method to enhance radiotherapy effect toward lung cancer. Radiation can completely abrogate local tumor angiogenesis, thus vasculogenesis may become the prime way to rebuilt new vasculature for residual and recurrent tumors. But the underlying mechanism is far from clear and merits further investigation. Some studies have recently shown lung cancer cells and tumor associated macrophages (TAMs) may promote vesculogenesis through a possible self-perpetuating positive loop between TLR4 /NF-κB and HIF-1α activated by Prx-1 that results in the recruitment and M2 phenotype polarization of TAM under tumor hypoxia. Our previous study have shown the radiosensibilization of β-elemene is related with inhibiting vessels of lung cancer， and HIF-1α and Prx-1 are molecular targets. So the present study plans to explore the synergy effect of β-elemene with radiation toward vasculogenesis, and the relationship with the positive loop between TLR4 /NF-ΚB and HIF-1α activated by Prx-1 under hypoxic circumstances induced by radiotherapy. We try to clarify whether this molecular loop is the underlying mechanism by which to promote lung cancer vasculogenesis induced by radiation and find critical targets. The aim of this research is to provid theoretical foundation for developing anti-vessels targeted therapy and to suggest β-elemene as anti-vascologenesis drug to enhance radiation effect.

英文关键词： β-elemene;radiation;lung cancer;tumor vasculogenesis;molecular mechanism