光动力疗法中肿瘤耐药性的靶向调控

Multidrug resistance (MDR) is responsible for treatment failure in cancer chemotherapy. Some natural flavonoid and chalcone products (e.g. chrysin and 2′,5′-dihydroxychalcone) not only can affect multidrug resistance proteins (MRP)-mediated drug efflux but also modulate cellular glutathione (GSH) levels. The dual synergistic action of chrysin and 2′,5′-dihydroxychalcone (2′,5′-DHC) on drug transporter inhibition and GSH depletion can provide a novel synergistic approach to sensitize cancer cells to anticancer therapy that relies on both intracellular drug accumulation and pro-oxidant effects. In particular, this newly identified dual action will provide an effective strategy to improve photodynamic therapy (PDT) which involves the administration of a photosensitizer followed by irradiating the disease site with visible light. Essentially, PDT is a unique oxidative therapy and its cytotoxicity is determined by photochemically generated cytotoxic reactive oxygen species (ROS) (e.g. singlet oxygen). The yield of cytotoxic oxygen species is governed by cellular photosensitizer uptake and cellular antioxidants. It can be hypothesized that synergistically targeting these two pathways (i.e. inhibiting drug efflux transporters to increase photosensitizer uptake and depleting cellular GSH to decrease ROS scavenge) will ultimately maximize PDT therapeutic potency and improve PDT outcomes. The goal of this project is to develop a new strategy of utilizing natural flavonoid and chalcone products that target and sensitize cancer to conventional PDT. The proposed study might provide a readily available remedy to improve the effectiveness of conventional PDT in treating MDR cancer.

多药耐受是肿瘤化疗失败的一个重要原因。某些天然黄酮(如5,7-二羟基黄酮，2′,5′-二羟基查耳酮)不仅可调控多药耐受蛋白（膜泵）介导的药物外流，还可影响细胞谷胱甘肽(GSH)水平。这种独特的双重作用可用于敏化肿瘤细胞，为调控依赖于细胞内药物聚集和氧化损伤机制的治疗方法（如光动力疗法）提供新思路。光动力疗法涉及注射光敏剂和局部照光，本质上是一种氧化损伤疗法，其肿瘤杀伤效应取决于肿瘤细胞内光敏剂受光照激发产生的具有细胞毒性的单态氧，其产额受细胞内光敏剂和抗氧化剂浓度的直接影响。研究显示多药耐受机制可导致光敏剂外流。据此可以假设抑制膜泵(减少光敏剂外流)和耗竭GSH(减少单态氧淬灭)的协同作用将有利于光动力疗法治疗耐药肿瘤。本项目旨在揭示这种协同作用与肿瘤多药耐受机制的相互作用规律，通过黄酮类化合物逆转肿瘤耐药性的某些性状，靶向调控光动力介导的单态氧产额，以提高光动力疗法治疗耐药肿瘤的疗效。

多药耐受是肿瘤治疗的一个棘手问题，耐药主要机制是癌细胞通过膜泵将药物泵出细胞，使其失去疗效。研究显示光敏剂也受外流控制。本项目旨在为依赖于细胞内光敏剂药物聚集的光动力疗法提供一个能够逃逸耐药机制和提高疗效的新策略。主要研究内容包括：探明多药耐药肿瘤细胞的膜转运蛋白对光敏剂选择性和光动力疗法的影响；探索能够逃逸外流机制的血管靶向光动力作用；同时还将研究扩展到光动力疗法治疗多药耐药菌局部感染。主要结果包括：揭示了二氢卟吩类光敏剂对细胞膜糖蛋白(P-gp)高表达的鼻咽癌细胞有效；证明我国自主研发的二氢卟吩类光敏剂YLG-1与国外同类光敏剂等效；修饰硅酞氰光敏剂提高靶向性和血管靶向光动力中的应用潜力。本项目为光动力疗法在多药耐受肿瘤和局部感染的应用提供一种新思路和新技术。项目执行期间已发表中英文论文十二篇和专利三项。