Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

/pdf/essential-versus-accessory-aspects-of-cell-death-25xcm4k522.pdf

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Stimuli-activatable photosensitizers (PSs) are highly desirable for photodynamic therapy (PDT) to selectively demolish tumor cells. On the other hand, lysosomes are emerging as attractive anticancer targets. Herein, four cyclometalated iridium(III)–β-carboline complexes with pH-responsive singlet oxygen (1O2) production and lysosome-specific imaging properties have been designed and synthesized. Upon visible light (425 nm) irradiation, they show highly selective phototoxicities against cancer cells. Notably, complex 2 ([Ir(N^C)2(N^N)](PF6) in which N^C = 2-phenylpyridine and N^N = 1-(2-benzimidazolyl)-β-carboline) displays a remarkably high phototoxicity index (PI = IC50 in the dark/IC50 in light) of >833 against human lung carcinoma A549 cells. Further studies show that 2-mediated PDT induces caspase-dependent apoptosis through lysosomal damage. The pH-responsive phosphorescence of complex 2 can be utilized to monitor the lysosomal integrity upon PDT, which provides a reliable and convenient method for in situ monitoring of therapeutic effect and real-time assessment of treatment outcome. Our work provides a strategy for the construction of highly effective multifunctional subcellular targeted photodynamic anticancer agents through rational structural modification of phosphorescent metal complexes.

/pdf/cyclometalated-iridium-iii-complexes-as-lysosome-targeted-3s187ao8dw.pdf

Cyclometalated iridium(III) complexes as lysosome-targeted photodynamic anticancer and real-time tracking agents

Lysosomal membrane permeabilization in cell death: concepts and challenges.

Microtubule-targeting agents and their impact on cancer treatment.

Combating apoptosis and multidrug resistant cancers by targeting lysosomes.

Background: Hormone-refractory prostate cancer (HRPC) is characterized by poor response to chemotherapy and high mortality, particularly among African American men when compared to other racial/ethnic groups. It is generally accepted that docetaxel, the standard of care for chemotherapy of HRPC, primarily exerts tumor cell death by inducing mitotic catastrophe and caspase-dependent apoptosis following inhibition of microtubule depolymerization. However, there is a gap in our knowledge of mechanistic events underlying docetaxel-induced caspaseindependent cell death, and the genes that antagonize this process. This knowledge is important for circumventing HRPC chemoresistance and reducing disparities in prostate cancer mortality. Results: We investigated mechanistic events associated with docetaxel-induced death in HRPC cell lines using various approaches that distinguish caspase-dependent from caspase-independent cell death. Docetaxel induced both mitotic catastrophe and caspase-dependent apoptosis at various concentrations. However, caspase activity was not essential for docetaxel-induced cytotoxicity since cell death associated with lysosomal membrane permeabilization still occurred in the presence of caspase inhibitors. Partial inhibition of docetaxel-induced cytotoxicity was observed after inhibition of cathepsin B, but not inhibition of cathepsins D and L, suggesting that docetaxel induces caspase-independent, lysosomal cell death. Simultaneous inhibition of caspases and cathepsin B dramatically reduced docetaxel-induced cell death. Ectopic expression of lens epithelium-derived growth factor p75 (LEDGF/p75), a stress survival autoantigen and transcription co-activator, attenuated docetaxel-induced lysosomal destabilization and cell death. Interestingly,

/pdf/docetaxel-induced-prostate-cancer-cell-death-involves-2mvbpd3u1x.pdf

Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75

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Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75