Institute for Surgical Research, Philipps University of Marburg, Baldingerstrasse, Marburg, Germany.
Curr Pharm Biotechnol. 2012 Sep;13(11):2228-34. doi: 10.2174/138920112802501962.
Discovery of small molecules able to induce several cellular self-killing mechanisms improved cancer therapy in the last years. Research focused on canonical apoptotic (mitochondria or death receptor related) pathways to induce cell death in several hematologic and solid malignancies, showing that treatment with different synthetic and natural compounds reactivates the cell death machinery previously silenced in resistant cancer cells. Besides the canonical apoptotic pathways, alternative pathways of cell death induction have recently been rediscovered as potential new targets for cancer therapy. Under certain conditions, protein folding can be disturbed causing an accumulation of unfolded proteins inside the endoplasmic reticulum (ER). This situation leads to stress ER, involving the transcriptional and translational machinery to induce the expression and post-transcriptional modifications of many factors involved in ER stress response mediated cell death. In this scenario, some apoptotic players like caspase 4 or caspase 12 start to control cell fate by inducing downstream cell death proteins. Recently, inhibitors of protein deacetylases have been demonstrated to potently induce this alternative cell death pathway and will be reviewed here.
近年来，能够诱导多种细胞自杀机制的小分子的发现改善了癌症治疗。研究集中在经典的凋亡（线粒体或死亡受体相关）途径上，以诱导几种血液系统和实体恶性肿瘤中的细胞死亡，表明用不同的合成和天然化合物治疗可以重新激活先前在耐药癌细胞中沉默的细胞死亡机制。除了经典的凋亡途径外，细胞死亡诱导的替代途径最近被重新发现为癌症治疗的潜在新靶点。在某些情况下，蛋白质折叠会受到干扰，导致内质网（ER）内未折叠蛋白质的积累。这种情况会导致内质网应激，涉及转录和翻译机制，以诱导参与内质网应激反应介导的细胞死亡的许多因素的表达和转录后修饰。在这种情况下，一些凋亡因子，如半胱天冬酶 4 或半胱天冬酶 12，开始通过诱导下游细胞死亡蛋白来控制细胞命运。最近，已经证明蛋白去乙酰化酶抑制剂能够有效地诱导这种替代的细胞死亡途径，本文将对此进行综述。
