Inhibition of Ca2+Influx Is Required for Mitochondrial Reactive Oxygen Species-Induced Endoplasmic Reticulum Ca2+Depletion and Cell Death in Leukemia Cells

2006 ◽  
Vol 70 (4) ◽  
pp. 1424-1434 ◽  
Author(s):  
Yicheng Zhang ◽  
Jonathan Soboloff ◽  
Ziping Zhu ◽  
Stuart A. Berger
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Leukemia Cells ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

scholarly journals Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mariachiara Buccarelli ◽  
Quintino Giorgio D’Alessandris ◽  
Paola Matarrese ◽  
Cristiana Mollinari ◽  
Michele Signore ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Strong Increase ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

Abstract Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

scholarly journals Survival Signaling by C-RAF: Mitochondrial Reactive Oxygen Species and Ca2+ Are Critical Targets

2008 ◽  
Vol 28 (7) ◽  
pp. 2304-2313 ◽  
Author(s):  
Andrey V. Kuznetsov ◽  
Julija Smigelskaite ◽  
Christine Doblander ◽  
Manickam Janakiraman ◽  
Martin Hermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Ros ◽  
Survival Signaling ◽  
First Time

ABSTRACT Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca2+. Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca2+ levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca2+, which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca2+ overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca2+ homeostasis.

Caspase-independent cell death without generation of reactive oxygen species in irradiated MOLT-4 human leukemia cells

2009 ◽  
Vol 255 (1-2) ◽  
pp. 61-68 ◽  
Author(s):  
Kengo Yoshida ◽  
Yoshiko Kubo ◽  
Yoichiro Kusunoki ◽  
Yukari Morishita ◽  
Hiroko Nagamura ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Oxygen Species ◽  
Human Leukemia Cells

scholarly journals Mitochondrial reactive oxygen species in cell death signaling

Biochimie ◽  
2002 ◽  
Vol 84 (2-3) ◽  
pp. 131-141 ◽  
Author(s):  
Christophe Fleury ◽  
Bernard Mignotte ◽  
Jean-Luc Vayssière
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Cell Death Signaling

scholarly journals Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3523-3533 ◽  
Author(s):  
Jamie Honeychurch ◽  
Waleed Alduaij ◽  
Mahsa Azizyan ◽  
Eleanor J. Cheadle ◽  
Helene Pelicano ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Nadph Oxidase ◽  
B Cell ◽  
Reactive Oxygen ◽  
Leukemia Cells ◽  
Oxygen Species ◽  
Type Ii ◽  
B Cell Malignancies ◽  
Anti Cd20

Abstract Monoclonal antibodies (mAbs) have revolutionized the treatment of B-cell malignancies. Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) in the target cell and the underlying mechanisms involved remain under-investigated. We recently demonstrated that certain mAbs (type II anti-CD20 and anti-HLA DR mAbs) potently evoked PCD through an actin-dependent, lysosome-mediated process. Here, we reveal that the induction of PCD by these mAbs, including the type II anti-CD20 mAb GA101 (obinutuzumab), directly correlates with their ability to produce reactive oxygen species (ROS) in human B-lymphoma cell lines and primary B-cell chronic lymphocytic leukemia cells. ROS scavengers abrogated mAb-induced PCD indicating that ROS are required for the execution of cell death. ROS were generated downstream of mAb-induced actin cytoskeletal reorganization and lysosome membrane permeabilization. ROS production was independent of mitochondria and unaffected by BCL-2 overexpression. Instead, ROS generation was mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These findings provide further insights into a previously unrecognized role for NADPH oxidase-derived ROS in mediating nonapoptotic PCD evoked by mAbs in B-cell malignancies. This newly characterized cell death pathway may potentially be exploited to eliminate malignant cells, which are refractory to conventional chemotherapy and immunotherapy.

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