巨泡式死亡（Methuosis, MO）是一种新型的非凋亡程序性细胞死亡方式，典型特征是胞浆中出现巨大型空泡并致细胞极度空泡化而死亡。课题组偶然发现异戊烯基黄酮类化合物Comd 1可引起多种肿瘤细胞发生MO，进而对多种结构的异戊烯基类化合物进行筛选，发现了多个MO诱导剂并形成如下认识：结构方面：异戊烯基取代对MO诱导是必须的；异戊烯基的取代类型和位置非常重要；生物方面：MO不依赖于凋亡途径；不同基因型的肿瘤细胞反应不同，Ras突变型细胞灵敏度更高；巨胞饮是空泡的来源；晚期内体和溶酶体融合受阻是空泡融合增大的原因。拟解决的关键科学问题：明确诱导MO的关键结构；确认对MO敏感的肿瘤类型；探索MO的关键调节因子及调控机制。研究意义：MO不依赖于凋亡途径，MO诱导剂有望成为凋亡诱导剂的补充和替代；MO对克服以巨胞饮为主要营养获取路线的肿瘤尤为重要；丰富细胞死亡途径和异戊烯基取代化合物活性研究内容。

Methuosis is one of the novel forms of non-apoptotic programmed cell death. The typical characteristic of methuosis is the accumulation of large cytoplasmic vacuoles and ultimately leading to extreme vacuolization and rupture of cells. It was found by accident that prenylated flavonoid Comd 1 could induce MO in several kinds of cancer cells. Further screening of diverse prenylated compounds resulted in the discovery of several other MO inducers. Based on our preliminary data, some points were clarified as follow: from structural considerations, the existence of prenyl is necessary for the induction of MO, the structure and substituted site of prenyls are important for the induction of MO. From biology considerations, MO is independent of apoptosis; the sensitivity of MO inducers is different in cancer cells with different genotype, cancer cells with mutant Ras gene are especially sensitive; the cytoplasmic vacuoles are derived from macropinocytosis; the fusion block of late endosome and lysosome induced the accumulation and expansion of vacuoles. Key issues need to be resolved in this project focus on: identify the key structure for inducing MO; clarify the genotype of cancer cells which are especially sensitive to MO; explore the key regulators and mechanisms related to MO. The significance of this project lies in: in case of MO is independent of apoptosis, hopefully MO inducers will provide alternative for apoptosis inducers in cancer treatment; MO is important to overcome cancers with micropinocytosis as nutrition acquiring route; study on MO will add new contents to cell death pathways and the bioactivities of prenylated compounds.