PPARα受体激动剂抗肺腺癌的活性研究

Chemotherapy is playing an important role in clinical treatment for lung adenocarcinoma. However,the present drugs pose a number of drawbacks including low target,high toxicity.It is of great importance for discovering drugs by new methods,because tradictional method fail to screening new drugs in short term. Peroxisome proliferator-activated receptor α (PPARα receptor) pathway is closely associated with tumor development.Our preliminary studies have confirmed PPARαreceptor pathway is downregulated obviousily in lung adenocarcinoma and several PPARαreceptor agonists were obstained through expression profiling analysis. antitumor activity of one of them had been tested in lung adenocarcinoma cells.Based on these observations, we postulate that PPAR receptor agnoist might act as novel drugs for lung adenocarcinoma treatment.This proposal attempts to answer a few questions: (a)Is really PPARα PPAR receptor agonist an antitumor drug?(b)What are the molecular pathways affected by PPARαreceptor and how PPARαreceptor works? Addressing these questions is important to enrich the disvery of drugs and further our understanding of the antitumor activities of PPARα PPAR receptor agonist and is critical for its evaluation as a novel anti-tumor agent.

化疗在肺腺癌的临床治疗中有重要地位，然而目前的化疗药物还存在着毒性大、靶向性不够好等缺陷，传统的药物发现方法又难以短期内对现有药物进行补充，故用新的方法寻找新的治疗药物有重要意义。过氧化物酶增殖激活α受体(PPARα受体)通路与肿瘤发生关系密切。本研究前期通过基因表达谱分析，发现肺腺癌PPARα受体通路表达明显下调；生物信息分析也筛选到几个PPARα受体激动剂类药物，并通过细胞试验初步证明其中一种候选药物可抑制肺腺癌细胞的生长。由此，我们推测靶向激动PPARα受体通路的药物是一类有前景的抗肺腺癌药物，拟通过实验验证：1）PPARα受体激动剂具有抑制肺腺癌的活性；2）构建PPARα受体调控网络以便进一步了解其药理基础。上述假说的证明有助于丰富药物筛选和药物发现的方法，也为提升PPARα受体激动剂为新的抗肺腺癌药物提供依据。

化疗是肺癌临床治疗的重要手段，但当前用于肺癌治疗的药物还存在着高毒性、靶向性差等方面的缺陷。由于传统方法难以在短期内筛选出新药，采用新的方法发现低毒的抗肺癌药物有着非常重要的意义。过氧化物酶增殖激活α受体(PPARα受体)通路在调节脂质与糖代谢、氧化应激等过程中起重要作用，与肿瘤发生关系密切。在前期工作中，本项目发现肺腺癌PPARα受体通路明显下调表达；采用生物信息学方法，我们也筛选到几个PPARα受体激动剂,并且其中一种候选的PPARα受体激动剂——苯扎贝特被证实可抑制肺腺癌细胞的生长。由此,我们提出靶向激动PPARα受体通路的药物是一类有前景的抗肺腺癌药物,苯扎贝特可能是其中一种抗肺腺癌药物。因此，为了验证这一假设，本项目在前期工作基础上,进行了体外抗增殖和细胞周期实验。分子对接表明，苯扎贝特能靶向作用于调控细胞周期进程的细胞周期蛋白依赖性激酶2（CDK2）。而且，我们发现苯扎贝特能明显下调CDK2的表达。荷瘤裸鼠模型也表明苯扎贝特可以在体内抑制肿瘤的生长。综上所述，苯扎贝特可能是一种肺腺癌治疗的候选药物，可以为进一步筛选新的肺癌治疗药物提供新的思路。