New type of cell death mechanism induced by chemotherapeutic agents

十年的深入研究揭示了诱导程序性细胞死亡（PCD）的几种机制。这些机制可以是半胱天冬酶依赖性的或半胱天冬酶非依赖性的。后一类包括半胱天冬酶非依赖性细胞凋亡（CIA），其使用细胞色素c以外的线粒体分子，以及其他细胞死亡模式，如自噬性细胞死亡、有丝分裂灾难或半胱天冬酶非依赖性坏死样细胞死亡（CIND）。我们已经报道了甲磺酸伊马替尼（IM）诱导Bcr-Abl^+白血病中的CIND，其由Omi/Htra 2的丝氨酸蛋白酶活性介导。在这里，我们报道了以下两篇有趣的论文。（1）HDAC抑制剂Depsipeptide在体外和体内均可诱导横纹肌样细胞发生自噬，这种自噬与AIF的转位有关。我们还发现缩肽在骨肉瘤细胞系中诱导自噬。（2）INNO-406（BCR-ABL/林恩双重特异性抑制剂）通过caspase介导和caspase非依赖途径诱导Bcr-Abl+细胞程序性死亡（PCD）。后一种途径包括半胱天冬酶非依赖性凋亡（CIA）和CIND，我们观察到CIA或CIND的倾向与细胞对半胱天冬酶活性的依赖性密切相关。此外，我们发现INNO-406促进自噬。氯喹对自噬的抑制增强了INNO-406和缩酚酸肽诱导的细胞死亡，表明自噬反应是细胞保护机制。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.