百秋李醇纳米靶向EGFR调控Ras/MEK/JNK信号通路抗肺癌的分子机制

EGFR plays an important role in the progression of lung cancer and is a therapeutic target for lung cancer. Our preliminary data indicated that the patchouli alcohol (PA), which is an active compound of Chinese herb “Huo Xiang” ( Pogostemon cablin Benth), can inhibit the proliferation of lung cancer cells A549 via down-regulating EGFR expression and suppressing MEK/JNK signaling pathway. Therefore, PA is a therapeutic candidate for the lung cancer, which targets to EGFR, but PA lacks specificity and target to lung cancer cells..In previous study, we screened a high-molecular polymer AA1 polypeptide that can actively recognize EGFR. We proposed the hypothesis that “Construction of an AA1- potassium alcohol nanometer drug delivery system based on the affinity characteristics of AA1 polypeptide and EGFR receptor will achieve the precise treatment”. In this study, a novel targeted drug delivery system of Chinese herb, AA1-Pyrrhenol will be established by chemical synthesis technology , which will actively recognize the lung cancer cell membrane EGFR receptors to enhance the anti-cancer effect of PA. Then the orthotopic transplantation of lung cancer and cell model, and molecular biology techniques will be applied to explore the molecular mechanisms of AA1-PA nanoparticles on lung cancer metastasis via inhibiting the Ras/MEK/JNK pathway. This research is of great significance for the exploration of molecular targeted therapy and its mechanism of Chinese herb or lung cancer, and will provide new methods and ideas for the study of integrative medicine on lung cancer treatment.

EGFR在肺癌进展中起重要作用，是肺癌重要的治疗靶点。前期研究发现中药藿香的有效成分百秋李醇能通过抑制EGFR和下游MEK/JNK信号通路的活化，抑制肺癌A549细胞增殖。因此，百秋李醇有可能成为肺癌EGFR靶向治疗的候选药物，但百秋李醇对肺癌细胞缺乏特异性、靶向性。.课题组前期筛选出了能够主动识别EGFR的高分子聚合物AA1多肽，我们提出假说“利用AA1多肽与EGFR受体的亲和性特征，构建AA1-百秋李醇纳米给药系统，达到精准治疗的目的”。本研究采用化学合成技术，制备主动识别肺癌细胞膜EGFR受体的新型中药靶向给药系统AA1-百秋李醇纳米粒，以提高百秋李醇抗肺癌效果；采用肺癌原位移植瘤和细胞模型及分子生物学技术，探讨AA1-百秋李醇纳米粒靶向EGFR抑制Ras/MEK/JNK通路抗肺癌的分子机制。这对探索肺癌的中药分子靶向治疗及机制具有重要意义，为中西医结合治疗肺癌提供新的方法和思路。

本课题旨在既往研究发现中药藿香有效成分百秋李醇有可能成为肺癌 EGFR 靶向治疗的候选药物，通过抑制EGFR和下游MEK/JNK的信号通路的活化，抑制肺癌A549细胞增殖的基础上，与美国南佛罗里达大学化学系合作，以肺癌细胞表面过度表达EGFR为靶点，构建出同时具有肿瘤主动靶向功能、体内长循环功能、药物可控释放的AA1多肽修饰的百秋李醇纳米粒，利用AA1多肽与肺癌细胞表面EGFR受体特异性结合，使药物特异性地靶向肺癌细胞，持续发挥靶向抗肿瘤作用。研究结果显示：(1)中药藿香有效成分百秋李醇具有抑制肺癌皮下移植瘤生长的作用，并且可以通过促进肺癌细胞自噬抑制其增殖；(2)以肺癌细胞膜表面过度表达EGFR为靶点，构建出同时具有肿瘤主动靶向功能、缓释作用的AA1多肽修饰的百秋李醇纳米粒；(3)证实AA1多肽修饰的百秋李醇纳米粒对肺癌的靶向作用；(4)利用AA1多肽与肺癌细胞膜表面EGFR受体特异性结合，使药物特异性的靶向肺癌细胞，持续发挥靶向抗肺癌肿瘤作用；(5)揭示AA1-百秋李醇纳米粒对肺癌侵袭转移的抑制作用；(6)揭示AA1-百秋李醇纳米靶向EGFR调控Ras-JNK-MAPK信号通路抗肺癌分子机制。总之，本研究从分子水平对靶向EGFR的百秋李醇纳米粒抗肺癌生长和转移的作用进行了综合评价，初步揭示百秋李醇纳米粒调控EGFR/Ras下游JNK-MAPK抗肺癌的分子机制，对探索肺癌的中药分子靶向治疗及机制具有重要的意义，也为中西医结合治疗肺癌提供新的方法和思路。