New type of cell death mechanism induced by chemotherapeutic agents

近十年的深入研究揭示了诱发程序性细胞死亡（PCD）的几种机制。这些机制可以是caspase依赖性的，也可以是caspase非依赖性的。后一类包括caspase非依赖性细胞凋亡（CIA），它使用线粒体分子而不是细胞色素c，以及其他细胞死亡模式，如自噬细胞死亡、有丝分裂灾难或caspase非依赖性坏死样细胞死亡（CIND）。我们已经报道，甲酸伊马替尼（IM）在Bcr-Abl^+白血病中诱导CIND，这是由Omi/Htra2的丝氨酸蛋白酶活性介导的。这里我们报道了以下两篇有趣的论文。(1)在体外和体内，Depsipeptide （HDAC抑制剂）均可诱导横纹肌样细胞自噬，且这种自噬与AIF易位有关。我们还发现沉积肽诱导骨肉瘤细胞系自噬。(2)INNO-406（一种特异性双BCR-ABL/Lyn抑制剂）通过caspase介导和caspase非依赖性途径诱导BCR-ABL +细胞系的程序性细胞死亡（PCD）。后一种途径包括caspase-independent apoptosis （CIA）和CIND，我们观察到CIA或CIND的倾向与细胞对caspase活性的依赖密切相关。此外，我们发现INNO-406促进自噬。氯喹抑制自噬可增强INNO-406和抑郁肽诱导的细胞死亡，表明自噬反应是细胞的保护机制。这些发现为实体瘤和急性白血病的生物学和治疗提供了新的见解。

A decade of intensive research has revealed several mechanisms that induce programmed cell death (PCD). These mechanisms can be caspase-dependent or caspase-independent. The latter category include caspase-independent apoptosis (CIA), which employs mitochondrial molecules other than cytochrome c, as well other modes of cell death such as autophagic cell death, mitotic catastrophe, or caspase-independent necrosis-like cell death (CIND) We have reported that imatinib mesylate (IM) induced CIND in Bcr-Abl^+ leukemias that is mediated by the serine protease activity of Omi/Htra2. Here we reported the following two interesting papers. (1)Depsipeptide (HDAC inhibitor) induces autophagy in rhabdoid cells both in vitro and in vivo and this autophagy is related with translocation of AIF. We also find that depsipeptide induce autophagy in osteosarcoma cell lines. (2)INNO-406 (a specific dual BCR-ABL/Lyn inhibitor) induce induces programmed cell death (PCD) in Bcr-Abl+ cell lines via both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and CIND, and we observed that the propensity towards CIA or CIND was strongly associated with cellular dependency on caspase activity. Moreover, we found that INNO-406 promotes autophagy. Inhibition of autophagy by chloroquine enhanced both INNO-406 and depsipeptide-induced cell death, indicating the autophagic response as the cell protective mechanism. These findings suggest new insights into the biology and therapy of solid tumors and acute leukemias.