光敏剂靶向内质网调控致死性自噬敏化癌细胞的作用及黄连素干预的研究

Endoplasmic reticulum (ER)-targeting photosensitizer-mediated photodynamic therapy (PDT) induces autophagy via both oxidative stress and ER stress. Activated moderately, autophagy functions as a protective mechanism and promotes the acquired resistance, whose enhancement may, however, initiates aturophagic cell death (ACD). Based on the principle of Traditional Chinese Medicine, our previous study has identified berberine, a drug for Clearing Heat and Removing Toxin, as a potent photosensitizer with high specifity in inducing ER stress. This study is aimed to determine the effect of berberine-mediated PDT on autophagy induction and the critical factor involved in deciding cell fate. This helps clarify the mechanism underlying ACD initiation and chemosensitization of colorectal cancer, offering a novel opportunity for the clinical application of PDT in the treatment of resistant colorectal cancer.

内质网（ER）靶向定位的光敏药物介导的光动力抗肿瘤疗法（photodynamic therapy，PDT）可通过氧化应激及ER应激双重机制激活自噬反应。低程度的细胞自噬作为细胞的保护机制，介导了获得性耐药的产生；而剧烈的自噬可诱导自噬性细胞死亡。课题前期我们在中医学“热毒”与肿瘤发生的启示下，针对清热解毒药类药物，发现了黄连中黄莲素的ER靶向光动力活性，本课题拟深入考察黄连素-PDT诱导的ER应激对自噬功能的影响，并探明黄连素-PDT调控自噬功能的关键靶基因即ER应激下游致死因子CHOP及相关信号分子对自噬功能的调控作用；旨在促生存自噬与促死亡自噬之间寻找到一个转换点（关键蛋白），通过对其干扰，达到诱导致死性自噬的目的，抑制肿瘤细胞多药耐药的形成，进一步探讨清热解毒的黄连素-PDT通过自噬增敏耐药性肿瘤细胞的分子机制，为临床应用光动力治疗耐药性肿瘤提供基础。

内质网（ER）靶向定位的光敏药物介导的光动力抗肿瘤疗法（photodynamic therapy，PDT）可通过氧化应激及ER应激双重机制激活自噬反应。低程度的细胞自噬作为细胞的保护机制，介导了获得性耐药的产生；而剧烈的自噬可诱导自噬性细胞死亡。本课题系统的研究了黄连中黄莲素的ER靶向光动力活性，深入考察黄连素-PDT诱导的ER应激对自噬功能的影响，并探明黄连素-PDT调控自噬功能的关键靶基因即ER应激下游致死因子CHOP及相关信号分子对自噬功能的调控作用；研究了促生存自噬与促死亡自噬及调控的分子机制，通过对其干扰，达到诱导致死性自噬的目的，抑制肿瘤细胞多药耐药的形成，进一步探讨清热解毒的黄连素-PDT通过自噬增敏耐药性肿瘤细胞的分子机制，为临床应用光动力治疗耐药性肿瘤提供基础。