硫化砷通过激活UPR-XBP1u促进伊立替康抑制胃癌作用的机制

胃癌是我国高发恶性肿瘤，晚期胃癌因缺乏有效药物治疗而预后极差。本课题组曾首次报道了传统中药雄黄主成分硫化砷的抗胃癌作用，我们近期研究发现硫化砷可增强胃癌常用化疗药IRN和L-OHP的作用，与IRN协同作用最强（CI<0.3）；临床研究中也发现硫化砷和IRN组合能给患者带来获益；硫化砷能上调XBP1u，造成Ubiquitin紊乱，抑制DNA修复过程，增加细胞对DNA损伤诱导剂IRN的敏感性。据此，我们认为：硫化砷通过激活UPR-XBP1u来抑制DNA损伤的修复，从而增强IRN杀伤胃癌细胞的效果。本课题拟从分子、细胞、动物和患者水平多维度深入研究硫化砷激活非经典UPR的机制及其在DNA损伤修复中的作用，最终明确硫化砷联合IRN协同抑制胃癌的机制。本项目是应用现代科技手段对传统中药作用机制的深入挖掘，将为扩大传统中药硫化砷的新的临床适应症提供强有力的理论支持，具有极大的经济效益和社会效益。

Gastric adenocarcinoma is a very aggressive and common malignancy in China. There are very limited treatment options and overall survival remains very poor. Our lab has studied the cytotoxic effect of Arsenic Sulfide (AS), the effective component of realgar in gastric adenocarcinoma and demonstrated that AS retains substantial activity against this challenging malignancy. We have also demonstrated that AS can enhance the cytotoxic effect of chemotherapeutics such as Irinotecan (IRN) and Oxaliplatin(L-OHP). AS and IRN combination exhibited a strong synergistic effect (CI <0.3); AS activates the non-classical UPR pathway to up-regulate XBP1u, causing Ubiquitin Stress, inhibiting the DNA repair process, and increasing the sensitivity of cancer cells to the DNA damage induced by IRN. Based on our data, we hypothesize that AS up-regulates XBP1u by activating ER Stress and inhibits the repair process of DNA damage, hence enhancing the cytotoxic effect of IRN in gastric cancer cells. We aim to study the mechanisms of AS in activating UPR and the role of non-classical UPR in DNA damage repair as well as the mechanisms of AS in promoting the cytotoxic effect of IRN in gastric cancer using cell lines, animals, and patient samples. This research project aims at an in-depth exploration of the traditional Chinese medicine AS on the mechanisms of its pharmacological action by applying modern scientific and technological tools, and establish foundational support for the expansion of new clinical indications of realgar, with excellent economic and social benefits.