Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL
Scott McCombJúlia Aguadé-GorgorióLena HarderBlerim MarovcaGunnar CarioCornelia EckertMartin SchrappeMartin StanullaArend von StackelbergJean‐Pierre BourquinBeat Bornhäuser
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Abstract:
More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials.Keywords:
Refractory (planetary science)
Genetically programmed cell death is a universal and fundamental cellular process in multicellular organisms. Apoptosis and necroptosis, two common forms of programmed cell death, play vital roles in maintenance of homeostasis in metazoans. Dysfunction of the regulatory machinery of these processes can lead to carcinogenesis or autoimmune diseases. Inappropriate death of essential cells can lead to organ dysfunction or even death; ischemia-reperfusion injury and neurodegenerative disorders are examples of this. Recently, novel forms of non-apoptotic programmed cell death have been identified. Although these forms of cell death play significant roles in both physiological and pathological conditions, the detailed molecular mechanisms underlying them are still poorly understood. Here, we discuss progress in using small molecules to dissect three forms of non-apoptotic programmed cell death: necroptosis, ferroptosis, and pyroptosis.
Pyroptosis
Apoptotic cell death
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Death events encoutered by cells have been always classified into two well-defined molecular pathways. Necrosis,
unregulated and passive process being the result of an accidental injury compromising the cell whilst apoptosis is a controlled,
and coordinated method profited by the organism as a clearance to remove senescent cells. Apoptosis and necrosis have been
deeply studied due to the close relation leading to cancer development when misfunctions occur in their mechanisms. Recenty
some cells have been showing a different pattern of cell death, sharing features with both known mechanisms. A new paradigm
in cell death has the potencial to revolutionise cell therapy offering a new insight to how the organism regulate its own fate:
Necroptosis.
UVB-induced apoptosis
RIPK1
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Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.
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Abstract Cell death contributes to the maintenance of homeostasis, but mounting evidence has confirmed the involvement of programmed cell death in some diseases. The concept of programmed cell death, which was coined several decades ago to refer to apoptosis, now also encompasses necroptosis, a newly characterized cell death program. Research on programmed cell death has become essential for the development of some new therapies. To study cell death signaling and its molecular mechanisms, new biochemical and fluorogenic approaches have been devised. Here, we first provide an overview of programmed cell death modes and the importance of dynamic cell death studies. Next, we focus on both apoptotic and necroptotic signaling and their mechanisms by providing a systematic review of all the methods and approaches that have been used. We emphasize the contribution of advanced approaches based on fluorescent probes, reporters, and Förster resonance energy transfer (FRET)‐based biosensors for studying programmed cell death. Because apoptosis and necroptosis signaling pathways share some effectors molecules, we discuss how these new tools could be used to discriminate between apoptosis and necroptosis. We also describe how we developed specific FRET‐based biosensors for detecting necroptosis. Finally, we touch on how dynamic measurement of biomolecules in living models will play a role in personalized prognosis and therapy.
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Necrosis is generally believed to be a passive cellular response to external damage. To date, it has been difficult to investigate the potential mechanisms of necrosis. Recently, a new pathway to necrosis has been described by Yuan and colleagues. This pathway, called necroptosis, is a form of cell death that leads to necrosis. A chemical compound, necrostatin‐1 (Nec‐1), specifically inhibits this non‐apoptotic cell death. Iodoacetate (IAA) is an irreversible inhibitor of glycolysis and has been used as a tool for inducing chemical ischemia. We hypothesize that Nec‐1 can confer protection in this model. In this study, we explored the protective effects of Nec‐1 on IAA‐induced ischemia in rat myoblastic H9c2 cells. These cells were exposed to DMEM containing 7.5% dialyzed fetal bovine serum in the presence of 10–100 uM IAA for 2 h followed by incubation with regular medium overnight. Cell proliferation was measured by MTS assays. IAA was found to induce cell death in a dose‐dependent manner. At 50 uM IAA, cell proliferation was 30% as the control level. The addition of 25 uM Nec‐1 significantly attenuated IAA‐induced cell death. The protective effect of Nec‐1 was also dose‐dependent. These results demonstrate for the first time that necroptosis is involved in IAA‐induced cell death (Supported by American Heart Association Southeast Affiliate, Department of Veterans Affairs Merit Review and NIH HL‐087271).
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Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ’s physiological function.For long,only apoptosis was considered as a sole form of programmed cell death.Recently necroptosis,a RIP1/RIP3-dependent programmed cell death,has been identified as an apoptotic backup cell death mechanism with necrotic morphology.The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past.However,only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions.Although the number of necroptosis initiators is increasing;however,interestingly,it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules.Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance.By targeting necroptosis and/or other parallel death pathways,a significant cell loss and thus a decrement in an organ’s physiological function can be prevented.
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Apoptosis is a prototype of regulated cell death and plays a crucial role in the development of various organs and maintaining tissue homeostasis. Recent studies have revealed that new types of regulated cell death, including necroptosis, ferroptosis, and pyroptosis are molecularly identified. In this review, we discuss the molecular mechanisms and the functions of new types of regulated cell death.
Pyroptosis
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Programmed cell death (PCD) occurs in several forms including apoptosis and necroptosis. Apoptosis is executed by the activation of caspases, while necroptosis is dependent on the receptor interacting protein kinase 3 (RIPK3). Precise control of cell death is crucial for tissue homeostasis. Indeed, necroptosis is triggered by caspase inhibition to ensure cell death. Here we identified a previously uncharacterized cell death pathway regulated by TAK1, which is unexpectedly provoked by inhibition of caspase activity and necroptosis cascades. Ablation of TAK1 triggers spontaneous death in macrophages. Simultaneous inhibition of caspases and RIPK3 did not completely restore cell viability. Previous studies demonstrated that loss of TAK1 in fibroblasts causes TNF-induced apoptosis and that additional inhibition of caspase leads to necroptotic cell death. However, we surprisingly found that caspase and RIPK3 inhibitions do not completely suppress cell death in Tak1-deficient cells. Mechanistically, the execution of the third cell death pathway in Tak1-deficient macrophages and fibroblasts were mediated by RIPK1-dependent rapid accumulation of reactive oxygen species (ROS). Conversely, activation of RIPK1 was sufficient to induce cell death. Therefore, loss of TAK1 elicits noncanonical cell death which is mediated by RIPK1-induced oxidative stress upon caspase and necroptosis inhibition to further ensure induction of cell death.
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Caspase 8
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Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.
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