Division of Radiation Effects, Korea Institute of Radiological and Medical Science, Seoul, Korea.
Int J Radiat Oncol Biol Phys. 2011 Mar 15;79(4):1196-205. doi: 10.1016/j.ijrobp.2010.10.025.
HSP27 or HSP25 negatively regulates apoptosis pathways after radiation or chemotherapeutic agents. Abrogation of HSP27 function may be a candidate target for overcoming radio- and chemoresistance.
Zerumbone (ZER), a cytotoxic component isolated from Zingiber zerumbet smith. Clonogenic survival assay and flow cytometry after Annexin V staining were performed to determine in vitro sensitization effects of ZER with ionizing radiation. A nude mouse xenografting system was also applied to detect in vivo radiosensitizing effects of ZER.
ZER produced cross-linking of HSP27, which was dependent on inhibition of the monomeric form of HSP27. ZER was directly inserted between the disulfide bond in the HSP27 dimer and modified normal HSP27 dimerization. Pretreatment with ZER before radiation inhibited the binding affinity between HSP27 and apoptotic molecules, such as cytochrome c and PKCδ, and induced sensitization in vitro and in an in vivo xenografted nude mouse system. Structural analogs lacking only the carbonyl group in ZER, such as α-humulene (HUM) and 8-hydroxy-humulen (8-OH-HUM), did not affect normal cross-linking of HSP27 and did not induce radiosensitization.
We suggest that altered cross-linking of HSP27 by ZER is a good strategy for abolishing HSP27-mediated resistance.
HSP27 或 HSP25 在受到辐射或化疗药物后负调控细胞凋亡途径。HSP27 功能的缺失可能是克服放射和化学耐药性的候选靶点。
姜黄烯（ZER）是从姜黄属植物中分离出来的一种细胞毒性成分。通过克隆存活实验和 Annexin V 染色后的流式细胞术，确定 ZER 与电离辐射的体外增敏作用。还应用裸鼠异种移植系统来检测 ZER 的体内放射增敏作用。
ZER 产生 HSP27 的交联，这依赖于抑制 HSP27 的单体形式。ZER 直接插入 HSP27 二聚体的二硫键之间，并修饰正常的 HSP27 二聚化。在辐射前用 ZER 预处理可抑制 HSP27 与凋亡分子（如细胞色素 c 和 PKCδ）之间的结合亲和力，并在体外和体内裸鼠异种移植系统中诱导增敏作用。结构类似物仅缺乏 ZER 中的羰基，如 α-葎草烯（HUM）和 8-羟基葎草烯（8-OH-HUM），不影响正常的 HSP27 交联，也不诱导放射增敏作用。
我们认为 ZER 改变 HSP27 的交联是消除 HSP27 介导的耐药性的一种很好的策略。
