Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology, Suzhou, China; Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Chem Biol Interact. 2019 May 1;304:131-138. doi: 10.1016/j.cbi.2019.03.011. Epub 2019 Mar 16.
Non-apoptotic cell-death induction is a potential strategy for cancer treatment. Cytoplasmic vacuolation-associated cell death represents a novel type of non-apoptotic cell-death. Here, we showed that isobavachalcone (IBC), a naturally occurring chalcone compound, selectively induced cell death with massive cytoplasmic vacuolation in some leukemic cells but not in normal peripheral blood cells. Although the IBC-induced cell death displayed certain apoptotic changes, the caspase inhibitor Z-VAD-FMK did not significantly suppress IBC-induced cell death. IBC-induced vacuoles are acidic in nature, as revealed by neutral red staining. However, these vacuoles could not be labeled by lysosome or mitochondrial trackers. Moreover, the knockdown of several autophagy-related genes, such as LC3, Beclin-1, and ATG7, did not inhibit IBC-induced vacuolation. Transmission electron microscope examination revealed that these vacuoles mainly derived from the endosome. Surprisingly, Vacuolar-type H + -ATPase inhibitors, weak bases, such as chloroquine and AKT inhibitors, markedly abrogated vacuolization but enhance IBC-induced cell death, suggesting that IBC-induced vacuolation and cell death go into different direction and the vacuolization is a protective action rather than a part of the death mechanism. In conclusion, by using IBC as a chemical probe, we provide new characteristics of methuosis-like cell death. Inducing methuosis-like cell death may represent a novel strategy to combat leukemia.
非凋亡性细胞死亡诱导是癌症治疗的一种潜在策略。细胞质空泡化相关的细胞死亡代表了一种新型的非凋亡性细胞死亡。在这里，我们表明，异甘草素（IBC），一种天然存在的查尔酮化合物，选择性地诱导一些白血病细胞发生大量细胞质空泡化的细胞死亡，但不会诱导正常外周血细胞发生死亡。虽然 IBC 诱导的细胞死亡显示出某些凋亡变化，但半胱天冬酶抑制剂 Z-VAD-FMK 并没有显著抑制 IBC 诱导的细胞死亡。IBC 诱导的空泡在性质上是酸性的，如中性红染色所揭示的。然而，这些空泡不能被溶酶体或线粒体示踪剂标记。此外，几种自噬相关基因（如 LC3、Beclin-1 和 ATG7）的敲低并没有抑制 IBC 诱导的空泡化。透射电子显微镜检查显示，这些空泡主要来源于内体。令人惊讶的是，液泡型 H+ -ATPase 抑制剂，如氯喹和 AKT 抑制剂等弱碱，显著阻断了空泡化但增强了 IBC 诱导的细胞死亡，表明 IBC 诱导的空泡化和细胞死亡进入不同的方向，空泡化是一种保护作用而不是死亡机制的一部分。总之，通过使用 IBC 作为化学探针，我们提供了类似细胞坏死的细胞死亡的新特征。诱导类似细胞坏死的细胞死亡可能代表了一种治疗白血病的新策略。
